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Abstract:

The present invention relates to
heterocyclyl-substituted-ethylamino-phenyl compounds of general formula
(I), wherein K-L-M-N, Z and R1, R2, R3, R4 are as
described in the claims methods for their preparation, medicaments
comprising these compounds as well as their use for the preparation of a
medicament for the treatment of humans or animals.

Claims:

1. Heterocyclyl-substituted-ethylamino-phenyl derivative of general
formula (I) ##STR00170## whereinK-L-M-N together
form═CH--X--Y═CH--; in which any suitable H may be substituted by
R6 and/or R7, and in which X is selected from NR8, O or S,
while Y is selected from N or CH;═CH--X--Y--C(O)--; in which any
suitable H may be substituted by R6 and in which one of X and Y is
NR8, while the other is selected from NR8a, S or
O;═CH--X--Y--C(O)--; in which one of X and Y is CH2, while the
other is selected from NR8, S or O, in which any suitable H may be
substituted by R6 and/or
R7;═CR6--N═N--C(O)--;═CR9--CH═CH--CH═C-
H--; in which any suitable H may be substituted by
R6;═CR9--CH═CH--CH═CR9a--; in which any
suitable H may be substituted by R6;═CH--X═Y--CH═CH--;
in which any suitable H may be substituted by R6 and/or R7, and
in which one of X or Y is selected from N, while the other is selected
from N or CH;═CH--X═Y--CH2--CH2--; in which any
suitable H may be substituted by R6 and/or R7, and in which one
of X or Y is selected from N, while the other is selected from N or
CH;═CH--X--Y--CH═CH--; in which any suitable H may be substituted
by R6 and/or R7, and in which one of X or Y is selected from
NR8, O or S while the other is selected from NR8a or
CH2;═CH--X--Y--CH2--CH2--; in which any suitable H may
be substituted by R6 and/or R7, and in which one of X or Y is
selected from NR8, O or S while the other is selected from NR8a
or CH2;═CH--X--CH2--Y═CH--; in which any suitable H may
be substituted by R6 and/or R7, and in which X is selected from
NR8, O or S while Y is selected from N or
CH;═CH--X--CH═Y--CH2--; in which any suitable H may be
substituted by R6 and/or R7, and in which X is selected from
NR8, O or S while Y is selected from N or
CH;═CH--N═CH--Y═CH--; in which any suitable H may be
substituted by R6 and/or
R7;═CH--X--CH2--Y--CH2--; in which any suitable H may
be substituted by R6 and/or R7, and in which one of X or Y is
selected from NR8, O or S while the other is selected from
NR8a, O, S or CH2;R1 and R2 each are independently
selected from the group consisting of hydrogen; or a linear or branched,
saturated or unsaturated, optionally at least mono-substituted aliphatic
radical; orR1 and R2 together with the bridging nitrogen atom
form an saturated or unsaturated, optionally at least mono-substituted 5-
or 6-membered-heterocyclic ring, which may be condensed with an
optionally at least mono-substituted mono- or polycyclic ringsystem;Z is
selected from--(CH2)n--, with n being 1, 2, 3 or
4;--O--(CH2)n--, with n being 1, 2, 3 or
4;--S--(CH2)n--, with n being 1, 2, 3 or
4;--(CH2)n--(CHR5)--(CH2)m, with n and m being
selected from 0, 1, 2 or 3 and m+n being 1, 2 or 3, with R5 being
selected from F, Cl, Br, I, OH, SH, or unsubstituted
C1-4-Alkyl;R3 and R4 are independently from each other
selected from hydrogen; halogen, OH, SH, NH2; a linear or branched,
saturated or unsaturated, optionally at least mono-substituted aliphatic
radical; or O--R with R being a linear or branched, saturated or
unsaturated, optionally at least mono-substituted aliphatic
radical;R6 and R7 are independently from each other selected
from hydrogen; halogen, OH, SH, NH2; an aliphatic radical, which is
linear or branched, saturated or unsaturated, and optionally at least
mono-substituted by F, Cl, Br, I, SH or OH; or O--R with R being an
aliphatic radical, which is linear or branched, saturated or unsaturated,
and optionally at least mono-substituted by F, Cl, Br, I, SH or
OH;R8 and R8a are independently from each other selected from
hydrogen; or an aliphatic radical, which is linear or branched, saturated
or unsaturated, and optionally at least mono-substituted by F, Cl, Br, I,
SH or OH;R9 and R9a are independently from each other selected
from an aliphatic radical, which is linear or branched, saturated or
unsaturated, and optionally at least mono-substituted by F, Cl, Br, I, SH
or OH; or O--R with R being an aliphatic radical, which is linear or
branched, saturated or unsaturated, and optionally at least
mono-substituted by F, Cl, Br, I, SH or OH; or R9 and R9a both
are identical and selected from F, or Cl;optionally in form of one of its
stereoisomers, preferably enantiomers or diastereomers, its racemate or
in form of a mixture of at least two of its stereoisomers, preferably
enantiomers or diastereomers, in any mixing ratio; in form of a salt,
preferably a physiologically acceptable salt thereof, or a corresponding
solvate, or N-Oxide, respectively;with the proviso thatif R1 and
R2 are both CH3, R3 and R4 are both H, K-L-M-N
together form ═CR9--CH═CH--CH═CR9a-- and one of
R9 or R9a is --CH═CH2, the other may not be
OCH3;and with the proviso thatif R1 and R2 are both H, one
of R3 and R4 is H, while the other is --O(C2H5),
K-L-M-N together form ═CR9--CR.sup.6.dbd.CH--CH═CH--, and
R9 is --OCH3, R6 may not be OCH.sub.3.

2. Compound according to claim 1, characterized in that the compound is a
compound according to Formula Ia ##STR00171## whereinA is a compound
selected from the following group ##STR00172## R1 and R2 each
are independently selected from the group consisting of hydrogen; or a
linear or branched, saturated or unsaturated, optionally at least
mono-substituted aliphatic radical; orR1 and R2 together with
the bridging nitrogen atom form an saturated or unsaturated, optionally
at least mono-substituted 5- or 6-membered-heterocyclic ring, which may
be condensed with an optionally at least mono-substituted mono- or
polycyclic ringsystem,R3 and R4 are independently from each
other selected from hydrogen; halogen, OH, SH, NH2; a linear or
branched, saturated or unsaturated, optionally at least mono-substituted
aliphatic radical; or O--R with R being a linear or branched, saturated
or unsaturated, optionally at least mono-substituted aliphatic
radical;R6 and R7 are independently from each other selected
from hydrogen; halogen, OH, SH, NH2; an aliphatic radical, which is
linear or branched, saturated or unsaturated, and optionally at least
mono-substituted by F, Cl, Br, I, SH or OH; or O--R with R being an
aliphatic radical, which is linear or branched, saturated or unsaturated,
and optionally at least mono-substituted by F, Cl, Br, I, SH or
OH;R8 and R8a are independently from each other selected from
hydrogen; or an aliphatic radical, which is linear or branched, saturated
or unsaturated, and optionally at least mono-substituted by F, Cl, Br, I,
SH or OH;R9 and R9a are independently from each other selected
from an aliphatic radical, which is linear or branched, saturated or
unsaturated, and optionally at least mono-substituted by F, Cl, Br, I, SH
or OH; or O--R with R being an aliphatic radical, which is linear or
branched, saturated or unsaturated, and optionally at least
mono-substituted by F, Cl, Br, I, SH or OH; or R9 and R9a both
are identical and selected from F, or Cl;with the proviso thatif R1
and R2 are both CH3, R3 and R4 are both H, A is
##STR00173## and one of R9 or R93 is --CH═CH2, the
other may not be OCH3;and with the proviso thatif R1 and
R2 are both H, one of R3 and R4 is H, while the other is
--O(C2H5), A is ##STR00174## and R9 is --OCH3,
R6 may not be OCH3 in the position marked with "*".

3. Compound according to claim 2, characterized in that the compound is a
compound according to Formula Ia, whereinA is a compound selected from
the following group ##STR00175## R1 and R2 each are
independently selected from the group consisting of hydrogen; or a linear
or branched, saturated or unsaturated, optionally at least
mono-substituted aliphatic radical; orR1 and R2 together with
the bridging nitrogen atom form an saturated or unsaturated, optionally
at least mono-substituted 5- or 6-membered-heterocyclic ring, which may
be condensed with an optionally at least mono-substituted mono- or
polycyclic ringsystem,R3 and R4 are independently from each
other selected from hydrogen; halogen, OH, SH, NH2; a linear or
branched, saturated or unsaturated, optionally at least mono-substituted
aliphatic radical; or O--R with R being a linear or branched, saturated
or unsaturated, optionally at least mono-substituted aliphatic
radical;R6 and R7 are independently from each other selected
from hydrogen; halogen, OH, SH, NH2; an aliphatic radical, which is
linear or branched, saturated or unsaturated, and optionally at least
mono-substituted by F, Cl, Br, I, SH or OH; or O--R with R being an
aliphatic radical, which is linear or branched, saturated or unsaturated,
and optionally at least mono-substituted by F, Cl, Br, I, SH or
OH;R8 and R8a are independently from each other selected from
hydrogen; or an aliphatic radical, which is linear or branched, saturated
or unsaturated, and optionally at least mono-substituted by F, Cl, Br, I,
SH or OH;R9 and R9a are independently from each other selected
from an aliphatic radical, which is linear or branched, saturated or
unsaturated, and optionally at least mono-substituted by F, Cl, Br, I, SH
or OH; or O--R with R being an aliphatic radical, which is linear or
branched, saturated or unsaturated, and optionally at least
mono-substituted by F, Cl, Br, I, SH or OH; or R9 and R9a both
are identical and selected from F, or Cl;with the proviso thatif R1
and R2 are both CH3, R3 and R4 are both H, A is
##STR00176## and with the proviso thatif R1 and R2 are both H,
one of R3 and R4 is H, while the other is --O(C2H5),
A is ##STR00177## and R9 is --OCH3, R6 may not be
OCH3 in the position marked with "*".

4. Compound according to claim 2 or 3, characterized in that the compound
is a compound according to Formula Ia, whereinA is a compound selected
from the following group ##STR00178## R1 and R2 each are
independently selected from the group consisting of hydrogen; or a linear
or branched, saturated or unsaturated, optionally at least
mono-substituted aliphatic radical; orR1 and R2 together with
the bridging nitrogen atom form an saturated or unsaturated, optionally
at least mono-substituted 5- or 6-membered-heterocyclic ring, which may
be condensed with an optionally at least mono-substituted mono- or
polycyclic ringsystem,R3 and R4 are independently from each
other selected from hydrogen; halogen, OH, SH, NH2; a linear or
branched, saturated or unsaturated, optionally at least mono-substituted
aliphatic radical; or O--R with R being a linear or branched, saturated
or unsaturated, optionally at least mono-substituted aliphatic
radical;R6 and R7 are independently from each other selected
from hydrogen; halogen, OH, SH, NH2; an aliphatic radical, which is
linear or branched, saturated or unsaturated, and optionally at least
mono-substituted by F, Cl, Br, I, SH or OH; or O--R with R being an
aliphatic radical, which is linear or branched, saturated or unsaturated,
and optionally at least mono-substituted by F, Cl, Br, I, SH or
OH;R8 and R9a are independently from each other selected from
hydrogen; or an aliphatic radical, which is linear or branched, saturated
or unsaturated, and optionally at least mono-substituted by F, Cl, Br, I,
SH or OH;R9 and R9a are independently from each other selected
from an aliphatic radical, which is linear or branched, saturated or
unsaturated, and optionally at least mono-substituted by F, Cl, Br, I, SH
or OH; or O--R with R being an aliphatic radical, which is linear or
branched, saturated or unsaturated, and optionally at least
mono-substituted by F, Cl, Br, I, SH or OH; or R9 and R9a both
are identical and selected from F, or Cl;with the proviso thatif R1
and R2 are both CH3, R3 and R4 are both H, A is
##STR00179## and one of R9 or R9a is --CH═CH2, the
other may not be OCH3;and with the proviso thatif R1 and
R2 are both H, one of R3 and R4 is H, while the other is
--O(C2H5), A is ##STR00180## and R9 is --OCH3,
R6 may not be OCH3 in the position marked with "*".

5. Compound according to claim 4, characterized in that the compound is a
compound according to Formula Ia, whereinA is a compound selected from
the following group ##STR00181## R1 and R2 each are
independently selected from the group consisting of hydrogen; or a linear
or branched, saturated or unsaturated, optionally at least
mono-substituted aliphatic radical; orR1 and R2 together with
the bridging nitrogen atom form an saturated or unsaturated, optionally
at least mono-substituted 5- or 6-membered-heterocyclic ring, which may
be condensed with an optionally at least mono-substituted mono- or
polycyclic ringsystem;R3 and R4 are independently from each
other selected from hydrogen; halogen, OH, SH, NH2; a linear or
branched, saturated or unsaturated, optionally at least mono-substituted
aliphatic radical; or O--R with R being a linear or branched, saturated
or unsaturated, optionally at least mono-substituted aliphatic
radical;R6 and R7 are independently from each other selected
from hydrogen; halogen, OH, SH, NH2; an aliphatic radical, which is
linear or branched, saturated or unsaturated, and optionally at least
mono-substituted by F, Cl, Br, I, SH or OH; or O--R with R being an
aliphatic radical, which is linear or branched, saturated or unsaturated,
and optionally at least mono-substituted by F, Cl, Br, I, SH or
OH;R8 is selected from hydrogen; or an aliphatic radical, which is
linear or branched, saturated or unsaturated, and optionally at least
mono-substituted by F, Cl, Br, I, SH or OH.

6. Compound according to claim 4, characterized in that the compound is a
compound according to Formula Ia, whereinA is a compound selected from
the following group ##STR00182## R1 and R2 each are
independently selected from the group consisting of hydrogen; or a linear
or branched, saturated or unsaturated, optionally at least
mono-substituted aliphatic radical; orR1 and R2 together with
the bridging nitrogen atom form an saturated or unsaturated, optionally
at least mono-substituted 5- or 6-membered-heterocyclic ring, which may
be condensed with an optionally at least mono-substituted mono- or
polycyclic ringsystem,R3 and R4 are independently from each
other selected from hydrogen; halogen, OH, SH, NH2; a linear or
branched, saturated or unsaturated, optionally at least mono-substituted
aliphatic radical; or O--R with R being a linear or branched, saturated
or unsaturated, optionally at least mono-substituted aliphatic
radical;R6 is selected from hydrogen; halogen, OH, SH, NH2; an
aliphatic radical, which is linear or branched, saturated or unsaturated,
and optionally at least mono-substituted by F, Cl, Br, I, SH or OH; or
O--R with R being an aliphatic radical, which is linear or branched,
saturated or unsaturated, and optionally at least mono-substituted by F,
Cl, Br, I, SH or OH;R9 and R9a are independently from each
other selected from an aliphatic radical, which is linear or branched,
saturated or unsaturated, and optionally at least mono-substituted by F,
Cl, Br, I, SH or OH; or O--R with R being an aliphatic radical, which is
linear or branched, saturated or unsaturated, and optionally at least
mono-substituted by F, Cl, Br, I, SH or OH; or R9 and R9a both
are identical and selected from F, or Cl;with the proviso thatif R1
and R2 are both CH3, R3 and R4 are both H, A is
##STR00183## and one of R9 or R6a is -CH═CH2, the
other may not be OCH3;and with the proviso thatif R1 and
R2 are both H, one of R3 and R4 is H, while the other is
--O(C2H5), A is ##STR00184## and R9 is --OCH3,
R6 may not be OCH3 in the position marked with "*".

7. Compound according to any one of claims 1 to 6, characterized in that
R1 and R2 each are independently selected from the group
consisting of hydrogen; or a linear or branched, optionally at least
mono-substituted C1-4-alkyl radical; orR1 and R2 together
with the bridging nitrogen atom form an saturated or unsaturated,
optionally at least mono-substituted 5- or 6-membered-heterocyclic
ring;preferably in thatR1 and R2 are each independently
selected from the group consisting of hydrogen; or a linear or branched
C1-4-alkyl radical; orR1 and R2 together with the bridging
nitrogen atom form an saturated or unsaturated, optionally at least
mono-substituted 5- or 6-membered-heterocyclic ring;more preferably in
thatR1 and R2 are each independently selected from the group
consisting of hydrogen, CH3, C2H5, C3H7 or
C4H9; orR1 and R2 together with the bridging nitrogen
atom form an saturated or unsaturated, optionally at least
mono-substituted 5- or 6-membered-heterocyclic ring, selected from
piperidine and pyrazole;

8. Compound according to any one of claims 1 to 7, characterized in that
R3 and R4 are independently from each other selected from
hydrogen; halogen, OH, SH, NH2; a linear or branched, optionally at
least mono-substituted C1-4-alkyl radical;or O--R with R being a
linear or branched, optionally at least mono-substituted C1-4-alkyl
radical;preferably in thatR3 and R4 are independently from each
other selected from H, F, Cl, Br, I, OH, SH, NH2, CH3,
C2H5, C3H7, C4H9, OCH3,
OC2H5, OC3H7 or OC4H.sub.9.more preferably in
thatR3 and R4 are H, OH, CH3, OCH.sub.3.

9. Compound according to any one of claims 1 to 5, characterized in that
R6 and R7 are independently from each other selected from
hydrogen; halogen, OH, SH, NH2; a C1-4-alkyl radical, which is
linear or branched, and optionally at least mono-substituted by F, Cl,
Br, I, SH or OH; or O--R with R being a C1-4-alkyl radical, which is
linear or branched, and optionally at least mono-substituted by F, Cl,
Br, I, SH or OH;preferably in thatR6 and R7 are independently
from each other selected from H, F, Cl, Br, I, OH, SH, NH2,
CH3, C2H5, C3H7, C4H9, OCH3,
OC2H5, OC3H7 or OC4H9;more preferably in
thatR6 and R7 are independently from each other selected from
H, or CH.sub.3.

10. Compound according to any one of claims 1 to 5, characterized in
thatR8 is selected from hydrogen; or a C1-4-alkyl radical,
which is linear or branched, and optionally at least mono-substituted by
F, Cl, Br, I, SH or OH;preferably in thatR8 is selected from H, F,
Cl, Br, I, OH, SH, NH2, CH3, C2H5, C3H7, or
C4H9;more preferably in thatR8 is selected from H or
CH.sub.3.

12. Compound according to any one of claims 1 to 4 and 6, characterized in
that R6 is selected from hydrogen; halogen, OH, SH, NH2; a
C1-4-alkyl radical, which is linear or branched, and optionally at
least mono-substituted by F, Cl, Br, I, SH or OH; or O--R with R being a
C1-4-alkyl radical, which is linear or branched, and optionally at
least mono-substituted by F, Cl, Br, I, SH or OH;preferably in
thatR6 is selected from H, F, Cl, Br, I, OH, SH, NH2, CH3,
C2H5, C3H7, C4H9, OCH3,
OC2H5, OC3H7 or OC4H9;more preferably in
thatR6 is H, or Cl.

13. Compound according to any one of claims 1 to 4 and 6, characterized in
that R9 and R9a are independently from each other selected from
a C1-4-alkyl radical, which is linear or branched, and optionally at
least mono-substituted by F, Cl, Br, I, SH or OH; or O--R with R being a
C1-4-alkyl radical, which is linear or branched, and optionally at
least mono-substituted by F, Cl, Br, I, SH or OH; or R9 and R9a
both are identical and selected from F, or Cl;preferably in thatR9
and R9a are independently from each other selected from CH3,
C2H5, C3H7, C4H9, OCH3,
OC2H5, OC3H7 or OC4H9; or R9 and
R9a both are identical and selected from F, or Cl;more preferably in
thatR9 and R9a are independently from each other selected from
CH3, or OCH3; or R9 and R9a both are identical and
selected from F, or Cl;most preferably in thatR9 and R9a are
both selected either from CH3, OCH3, F, or Cl.

14. Compounds according to one or more of claims 1 to 4 and 6, selected
from[2-(2',6'-Dimethyl-biphenyl-3-yl)-ethyl]-dimethyl-amine,[2-(2',6'-Dim-
ethyl-biphenyl-3-yl)-ethyl]-methyl-amine,[2-(2',6'-Dimethyl-biphenyl-3-yl)-
-ethyl]-diethyl-amine,[2-(2',6'-Dimethyl-biphenyl-3-yl)-ethyl]-dipropyl-am-
ine,[2-(2',6'-Dimethoxy-biphenyl-3-yl)-ethyl]-dimethyl-amine,[2-(2',6'-Dim-
ethoxy-biphenyl-3-yl)-ethyl]-methyl-amine,[2-(2',6'-Dimethoxy-biphenyl-3-y-
l)-ethyl]-diethyl-amine,[2-(2',6'-Dimethoxy-biphenyl-3-yl)-ethyl]-dipropyl-
-amine,[2-(2'-Methoxy-biphenyl-3-yl)-ethyl]-dimethyl-amine,[2-(2'-Methoxy--
biphenyl-3-yl)-ethyl]-methyl-amine,Diethyl-[2-(2'-methoxy-biphenyl-3-yl)-e-
thyl]-amine,[2-(2'-Methoxy-biphenyl-3-yl)-ethyl]-dipropyl-amine,2-(2',6'-D-
imethoxy-biphenyl-3-yl)-ethylamine,[2-(6'-Chloro-2'-methoxy-biphenyl-3-yl)-
-ethyl]-dimethyl-amine,[2-(6'-Chloro-2'-methoxy-biphenyl-3-yl)-ethyl]-meth-
yl-amine,[2-(2'-Methoxy-2-methyl-biphenyl-3-yl)-ethyl]-dimethyl-amine,[2-(-
2'-Methoxy-6-methyl-biphenyl-3-yl)-ethyl]-dimethyl-amine,
or[2-(2',6'-Bis-trifluoromethyl-biphenyl-3-yl)-ethyl]-dimethyl-amine;
or2-(2',6'-Dichloro-biphenyl-3-yl)-ethyl]dimethyl-amine,
or[2-(2',6'-Difluoro-biphenyl-3-yl)-ethyl]dimethyl-amine;
or{2-[3-(2-Methoxy-pyridin-3-yl)-phenyl]-ethyl}-dimethyl-amine,
or{2-[3-(2-Methoxy-pyridin-3-yl)-phenyl]-ethyl}-methyl-amine;optionally
in form of a salt, preferably a physiologically acceptable salt, more
preferably in form of a physiologically acceptable acid addition salt,
most preferably a hydrochloride salt, or a corresponding solvate, or
N-Oxide.

15. Process for the preparation of compounds according to claim 1,
characterized in that a compound of general formula (VI) ##STR00185##
wherein R1, R2, R3, R4 and Z are as defined in claim
1, and X represents halogen, preferably Br, or an O-triflate group, is
reacted with a compound of general formula VII or VIIa ##STR00186##
wherein K, L, M, and N are as defined in claim 1, to form a compound
according to formula I, preferably in presence of a catalyst.

16. Process according to claim 15, characterized in thata) the catalyst is
a palladium catalyst with or without a ligand, and/orb) the reaction is
carried out in presence of at least one base, selected from organic or
inorganic bases and/orc) the reaction is carried out in a suitable
reaction medium selected from ethers, alcohols, hydrocarbons or other
organic solvents.

17. Medicament comprising at least one compound according to formula I,
##STR00187## whereinK-L-M-N together form═CH--X--Y═CH--; in which
any suitable H may be substituted by R6 and/or R7, and in which
X is selected from NR8, O or S, while Y is selected from N or
CH;═CH--X--Y--C(O)--; in which any suitable H may be substituted by
R6 and in which one of X and Y is NR8, while the other is
selected from NR8a, S or O;═CH--X--Y--C(O)--; in which one of X
and Y is CH2, while the other is selected from NR8, S or O, in
which any suitable H may be substituted by R6 and/or
R7;═CR6--N═N--C(O)--;═CR9--CH═CH--CH═C-
H--; in which any suitable H may be substituted by
R6;═CR9--CH═CH--CH═CR9a--; in which any
suitable H may be substituted by R6;═CH--X═Y--CH═CH--;
in which any suitable H may be substituted by R6 and/or R7, and
in which one of X or Y is selected from N, while the other is selected
from N or CH;═CH--X═Y--CH2--CH2--; in which any
suitable H may be substituted by R6 and/or R7, and in which one
of X or Y is selected from N, while the other is selected from N or
CH;═CH--X--Y--CH═CH--; in which any suitable H may be substituted
by R6 and/or R7, and in which one of X or Y is selected from
NR8, O or S while the other is selected from NR8a or
CH2;═CH--X--Y--CH2--CH2--; in which any suitable H may
be substituted by R6 and/or R7, and in which one of X or Y is
selected from NR8, O or S while the other is selected from NR8a
or CH2;═CH--X--CH2--Y═CH--; in which any suitable H may
be substituted by R6 and/or R7, and in which X is selected from
NR8, O or S while Y is selected from N or
CH;═CH--X--CH═Y--CH2--; in which any suitable H may be
substituted by R6 and/or R7, and in which X is selected from
NR8, O or S while Y is selected from N or
CH;═CH--N═CH--Y═CH--; in which any suitable H may be
substituted by R6 and/or
R7;═CH--X--CH2--Y--CH2--; in which any suitable H may
be substituted by R6 and/or R7, and in which one of X or Y is
selected from NR8, O or S while the other is selected from
NR8a, O, S or CH2;R1 and R2 each are independently
selected from the group consisting of hydrogen; or a linear or branched,
saturated or unsaturated, optionally at least mono-substituted aliphatic
radical; orR1 and R2 together with the bridging nitrogen atom
form an saturated or unsaturated, optionally at least mono-substituted 5-
or 6-membered-heterocyclic ring, which may be condensed with an
optionally at least mono-substituted mono- or polycyclic ringsystem;Z is
selected from--(CH2)n--, with n being 1, 2, 3 or
4;--O--(CH2)n--, with n being 1, 2, 3 or
4;--S--(CH2)n--, with n being 1, 2, 3 or
4;(CH2)n--(CHR5)--(CH2)m, with n and m being
selected from 0, 1, 2 or 3 and m+n being 1, 2 or 3, with R5 being
selected from F, Cl, Br, I, OH, SH, or unsubstituted
C1-4-Alkyl;R3 and R4 are independently from each other
selected from hydrogen; halogen, OH, SH, NH2; a linear or branched,
saturated or unsaturated, optionally at least mono-substituted aliphatic
radical; or O--R with R being a linear or branched, saturated or
unsaturated, optionally at least mono-substituted aliphatic
radical;R6 and R7 are independently from each other selected
from hydrogen; halogen, OH, SH, NH2; an aliphatic radical, which is
linear or branched, saturated or unsaturated, and optionally at least
mono-substituted by F, Cl, Br, I, SH or OH; or O--R with R being an
aliphatic radical, which is linear or branched, saturated or unsaturated,
and optionally at least mono-substituted by F, Cl, Br, I, SH or
OH;R8 and R8a are independently from each other selected from
hydrogen; or an aliphatic radical, which is linear or branched, saturated
or unsaturated, and optionally at least mono-substituted by F, Cl, Br, I,
SH or OH;R9 and R9a are independently from each other selected
from an aliphatic radical, which is linear or branched, saturated or
unsaturated, and optionally at least mono-substituted by F, Cl, Br, I, SH
or OH; or O--R with R being an aliphatic radical, which is linear or
branched, saturated or unsaturated, and optionally at least
mono-substituted by F, Cl, Br, I, SH or OH; or R9 and Re9a both
are identical and selected from F, or Cl;optionally in form of one of its
stereoisomers, preferably enantiomers or diastereomers, its racemate or
in form of a mixture of at least two of its stereoisomers in any mixing
ratio; in form of a salt, preferably a physiologically acceptable salt
thereof, or a solvate, or N-Oxide, respectively, and optionally one or
more pharmaceutically acceptable adjuvants.

18. Medicament according to claim 17, comprising at least one compound
according to formula Ia, ##STR00188## whereinA is a compound selected
from the following group ##STR00189## R1 and R2 each are
independently selected from the group consisting of hydrogen; or a linear
or branched, saturated or unsaturated, optionally at least
mono-substituted aliphatic radical; orR1 and R2 together with
the bridging nitrogen atom form an saturated or unsaturated, optionally
at least mono-substituted 5- or 6-membered-heterocyclic ring, which may
be condensed with an optionally at least mono-substituted mono- or
polycyclic ringsystem,R3 and R4 are independently from each
other selected from hydrogen; halogen, OH, SH, NH2; a linear or
branched, saturated or unsaturated, optionally at least mono-substituted
aliphatic radical; or O--R with R being a linear or branched, saturated
or unsaturated, optionally at least mono-substituted aliphatic
radical;R6 and R7 are independently from each other selected
from hydrogen; halogen, OH, SH, NH2; an aliphatic radical, which is
linear or branched, saturated or unsaturated, and optionally at least
mono-substituted by F, Cl, Br, I, SH or OH; or O--R with R being an
aliphatic radical, which is linear or branched, saturated or unsaturated,
and optionally at least mono-substituted by F, Cl, Br, I, SH or
OH;R8 and R8a are independently from each other selected from
hydrogen; or an aliphatic radical, which is linear or branched, saturated
or unsaturated, and optionally at least mono-substituted by F, Cl, Br, I,
SH or OH;R9 and R9a are independently from each other selected
from an aliphatic radical, which is linear or branched, saturated or
unsaturated, and optionally at least mono-substituted by F, Cl, Br, I, SH
or OH; or O--R with R being an aliphatic radical, which is linear or
branched, saturated or unsaturated, and optionally at least
mono-substituted by F, Cl, Br, I, SH or OH; or R9 and R9a both
are identical and selected from F, or Cl;optionally in form of one of its
stereoisomers, preferably enantiomers or diastereomers, its racemate or
in form of a mixture of at least two of its stereoisomers in any mixing
ratio, in form of a salt, preferably a physiologically acceptable salt
thereof, or a solvate, or N-Oxide, respectively, and optionally one or
more pharmaceutically acceptable adjuvants.

19. Medicament according to any of claim 17 or 18, comprising at least one
compound according to formula Ia, ##STR00190## whereinA is a compound
selected from the following group ##STR00191## R1 and R2 each
are independently selected from the group consisting of hydrogen; or a
linear or branched, saturated or unsaturated, optionally at least
mono-substituted aliphatic radical; orR1 and R2 together with
the bridging nitrogen atom form an saturated or unsaturated, optionally
at least mono-substituted 5- or 6-membered-heterocyclic ring, which may
be condensed with an optionally at least mono-substituted mono- or
polycyclic ring system,R3 and R4 are independently from each
other selected from hydrogen; halogen, OH, SH, NH2; a linear or
branched, saturated or unsaturated, optionally at least mono-substituted
aliphatic radical; or O--R with R being a linear or branched, saturated
or unsaturated, optionally at least mono-substituted aliphatic
radical;R6 is selected from hydrogen; halogen, OH, SH, NH2; an
aliphatic radical, which is linear or branched, saturated or unsaturated,
and optionally at least mono-substituted by F, Cl, Br, I, SH or OH; or
O--R with R being an aliphatic radical, which is linear or branched,
saturated or unsaturated, and optionally at least mono-substituted by F,
Cl, Br, I, SH or OH;R9 and R9a are independently from each
other selected from an aliphatic radical, which is linear or branched,
saturated or unsaturated, and optionally at least mono-substituted by F,
Cl, Br, I, SH or OH; or O--R with R being an aliphatic radical, which is
linear or branched, saturated or unsaturated, and optionally at least
mono-substituted by F, Cl, Br, I, SH or OH; or R9 and R9a both
are identical and selected from F, or Cl;optionally in form of one of its
stereoisomers, preferably enantiomers or diastereomers, its racemate or
in form of a mixture of at least two of its stereoisomers in any mixing
ratio, in form of a salt, preferably a physiologically acceptable salt
thereof, or a solvate, or N-Oxide, respectively, and optionally one or
more pharmaceutically acceptable adjuvants.

20. Medicament comprising at least one compound according to claims 1-14,
optionally in form of one of its stereoisomers, preferably enantiomers or
diastereomers, its racemate or in form of a mixture of at least two of
its stereoisomers in any mixing ratio, in form of a salt, preferably a
physiologically acceptable salt thereof, or a solvate, or N-Oxide,
respectively, and optionally one or more pharmaceutically acceptable
adjuvants.

21. Use of at least one compound according to formula I, ##STR00192##
whereinK-L-M-N together form═CH--X--Y═CH--; in which any suitable
H may be substituted by R6 and/or R7, and in which X is
selected from NR8, O or S, while Y is selected from N or
CH;═CH--X--Y--C(O)--; in which any suitable H may be substituted by
R6 and in which one of X and Y is NR8, while the other is
selected from NR8a, S or O;═CH--X--Y--C(O)--; in which one of X
and Y is CH2, while the other is selected from NR8, S or O, in
which any suitable H may be substituted by R6 and/or
R7;═CR6--N═N--C(O)--;═CR9--CH═CH--CH═C-
H--; in which any suitable H may be substituted by
R6;═CR9--CH═CH--CH═CR9a--; in which any
suitable H may be substituted by R6;═CH--X═Y--CH═CH--;
in which any suitable H may be substituted by R6 and/or R7, and
in which one of X or Y is selected from N, while the other is selected
from N or CH;═CH--X═Y--CH2--CH2--; in which any
suitable H may be substituted by R6 and/or R7, and in which one
of X or Y is selected from N, while the other is selected from N or
CH;═CH--X--Y--CH═CH--; in which any suitable H may be substituted
by R6 and/or R7, and in which one of X or Y is selected from
NR8, O or S while the other is selected from NR8a or
CH2;═CH--X--Y--CH2--CH2--; in which any suitable H may
be substituted by R6 and/or R7, and in which one of X or Y is
selected from NR8, O or S while the other is selected from NR8a
or CH2;═CH--X--CH2--Y═CH--; in which any suitable H may
be substituted by R6 and/or R7, and in which X is selected from
NR8, O or S while Y is selected from N or
CH;═CH--X--CH═Y--CH2--; in which any suitable H may be
substituted by R6 and/or R7, and in which X is selected from
NR8, O or S while Y is selected from N or
CH;═CH--N═CH--Y═CH--; in which any suitable H may be
substituted by R6 and/or
R7;═CH--X--CH2--Y--CH2--; in which any suitable H may
be substituted by R6 and/or R7, and in which one of X or Y is
selected from NR8, O or S while the other is selected from
NR8a, O, S or CH2;R1 and R2 each are independently
selected from the group consisting of hydrogen; or a linear or branched,
saturated or unsaturated, optionally at least mono-substituted aliphatic
radical; orR1 and R2 together with the bridging nitrogen atom
form an saturated or unsaturated, optionally at least mono-substituted 5-
or 6-membered-heterocyclic ring, which may be condensed with an
optionally at least mono-substituted mono- or polycyclic ringsystem;Z is
selected from--(CH2)n--, with n being 1, 2, 3 or
4;--O--(CH2)n--, with n being 1, 2, 3 or 4;--S--(CH2)
n--, with n being 1, 2, 3 or
4;(CH2)n--(CHR5)--(CH2)m, with n and m being
selected from 0, 1, 2 or 3 and m+n being 1, 2 or 3, with R5 being
selected from F, Cl, Br, I, OH, SH, or unsubstituted
C1-4-Alkyl;R3 and R4 are independently from each other
selected from hydrogen; halogen, OH, SH, NH2; a linear or branched,
saturated or unsaturated, optionally at least mono-substituted aliphatic
radical; or O--R with R being a linear or branched, saturated or
unsaturated, optionally at least mono-substituted aliphatic
radical;R6 and R7 are independently from each other selected
from hydrogen; halogen, OH, SH, NH2; an aliphatic radical, which is
linear or branched, saturated or unsaturated, and optionally at least
mono-substituted by F, Cl, Br, I, SH or OH; or O--R with R being an
aliphatic radical, which is linear or branched, saturated or unsaturated,
and optionally at least mono-substituted by F, Cl, Br, I, SH or
OH;R8 and R8a are independently from each other selected from
hydrogen; or an aliphatic radical, which is linear or branched, saturated
or unsaturated, and optionally at least mono-substituted by F, Cl, Br, I,
SH or OH;R9 and R9a are independently from each other selected
from an aliphatic radical, which is linear or branched, saturated or
unsaturated, and optionally at least mono-substituted by F, Cl, Br, I, SH
or OH; or O--R with R being an aliphatic radical, which is linear or
branched, saturated or unsaturated, and optionally at least
mono-substituted by F, Cl, Br, I, SH or OH; or R9 and R9a both
are identical and selected from F, or Cl;optionally in form of one of its
stereoisomers, preferably enantiomers or diastereomers, its racemate or
in form of a mixture of at least two of its stereoisomers in any mixing
ratio, in form of a salt, preferably a physiologically acceptable salt
thereof, or a solvate, or N-Oxide, respectively, for the manufacture of a
medicament for the treatment of a 5-HT7 mediated disease or
condition.

22. Use according to claim 21 of at least one compound according to
formula Ia, ##STR00193## whereinA is a compound selected from the
following group ##STR00194## R1 and R2 each are independently
selected from the group consisting of hydrogen; or a linear or branched,
saturated or unsaturated, optionally at least mono-substituted aliphatic
radical; orR1 and R2 together with the bridging nitrogen atom
form an saturated or unsaturated, optionally at least mono-substituted 5-
or 6-membered-heterocyclic ring, which may be condensed with an
optionally at least mono-substituted mono- or polycyclic
ringsystem,R3 and R4 are independently from each other selected
from hydrogen; halogen, OH, SH, NH2; a linear or branched, saturated
or unsaturated, optionally at least mono-substituted aliphatic radical;
or O--R with R being a linear or branched, saturated or unsaturated,
optionally at least mono-substituted aliphatic radical;R6 and
R7 are independently from each other selected from hydrogen;
halogen, OH, SH, NH2; an aliphatic radical, which is linear or
branched, saturated or unsaturated, and optionally at least
mono-substituted by F, Cl, Br, I, SH or OH; or O--R with R being an
aliphatic radical, which is linear or branched, saturated or unsaturated,
and optionally at least mono-substituted by F, Cl, Br, I, SH or
OH;R8 and R8a are independently from each other selected from
hydrogen; or an aliphatic radical, which is linear or branched, saturated
or unsaturated, and optionally at least mono-substituted by F, Cl, Br, I,
SH or OH;R9 and R9a are independently from each other selected
from an aliphatic radical, which is linear or branched, saturated or
unsaturated, and optionally at least mono-substituted by F, Cl, Br, I, SH
or OH; or O--R with R being an aliphatic radical, which is linear or
branched, saturated or unsaturated, and optionally at least
mono-substituted by F, Cl, Br, I, SH or OH; or R9 and R9a both
are identical and selected from F, or Cl;optionally in form of one of its
stereoisomers, preferably enantiomers or diastereomers, its racemate or
in form of a mixture of at least two of its stereoisomers in any mixing
ratio, in form of a salt, preferably a physiologically acceptable salt
thereof, or a solvate, or N-Oxide, respectively, for the manufacture of a
medicament for the treatment of a 5-HT7 mediated disease or
condition.

23. Use according to any of claim 21 or 22 of at least one compound
according to formula Ia, ##STR00195## whereinA is a compound selected
from the following group ##STR00196## R1 and R2 each are
independently selected from the group consisting of hydrogen; or a linear
or branched, saturated or unsaturated, optionally at least
mono-substituted aliphatic radical; orR1 and R2 together with
the bridging nitrogen atom form an saturated or unsaturated, optionally
at least mono-substituted 5- or 6-membered-heterocyclic ring, which may
be condensed with an optionally at least mono-substituted mono- or
polycyclic ringsystem,R3 and R4 are independently from each
other selected from hydrogen; halogen, OH, SH, NH2; a linear or
branched, saturated or unsaturated, optionally at least mono-substituted
aliphatic radical; or O--R with R being a linear or branched, saturated
or unsaturated, optionally at least mono-substituted aliphatic
radical;R6 is selected from hydrogen; halogen, OH, SH, NH2; an
aliphatic radical, which is linear or branched, saturated or unsaturated,
and optionally at least mono-substituted by F, Cl, Br, I, SH or OH; or
O--R with R being an aliphatic radical, which is linear or branched,
saturated or unsaturated, and optionally at least mono-substituted by F,
Cl, Br, I, SH or OH;R9 and R9a are independently from each
other selected from an aliphatic radical, which is linear or branched,
saturated or unsaturated, and optionally at least mono-substituted by F,
Cl, Br, I, SH or OH; or O--R with R being an aliphatic radical, which is
linear or branched, saturated or unsaturated, and optionally at least
mono-substituted by F, Cl, Br, I, SH or OH; or R9 and R9a both
are identical and selected from F, or Cl;optionally in form of one of its
stereoisomers, preferably enantiomers or diastereomers, its racemate or
in form of a mixture of at least two of its stereoisomers in any mixing
ratio, in form of a salt, preferably a physiologically acceptable salt
thereof, or a solvate, or N-Oxide, respectively, for the manufacture of a
medicament for the treatment of a 5-HT7 mediated disease or
condition.

24. Use of at least one compound according to claims 1-14, optionally in
form of one of its stereoisomers, preferably enantiomers or
diastereomers, its racemate or in form of a mixture of at least two of
its stereoisomers in any mixing ratio, or a physiologically acceptable
salt thereof, or a solvate, respectively, for the manufacture of a
medicament for the treatment of a 5-HT7 mediated disease or
condition.

25. Use according to any of claims 21 to 24 wherein the disease is pain,
preferably visceral pain, chronic pain, cancer pain, migraine, acute pain
or neuropathic pain, more prefearably neuropathic pain, allodynia or
hyperalgesia.

Description:

[0001]The present invention relates to
heterocyclyl-substituted-ethylamino-phenyl compounds of general formula
(I), methods for their preparation, medicaments comprising these
compounds as well as their use for the preparation of a medicament for
the treatment of humans or animals

[0002]The search for new therapeutic agents has been greatly aided in
recent years by better understanding of the structure of proteins and
other biomolecules associated with target diseases. One important class
of proteins that has been the subject of extensive study is the family of
5-hydroxytryptamine (serotonin, 5-HT) receptors. The 5-HT7 receptor
discovered in 1993 belongs to this family and has attracted great
interest as a valuable new drug target (Terron, J. A. Idrugs, 1998, vol.
1, no. 3, pages 302-310: "The 5HT7 receptor: A target for novel
therapeutic avenues?").

[0003]5-HT7 receptors have been cloned from rat, mouse, guinea pig
and human cDNA and exhibit a high degree of interspecies homology
(approx. 95%), but it is unique in that it has a low sequence homology
with other 5-HT receptors (less than 40%). Its expression pattern, in
particular structures of the central nervous system (CNS) (highest in
hypothalamus (in particular suprachiasmatic nuclei) and thalamus) and
other peripheral tissues (spleen, kidney, intestinal, heart and coronary
arthery), implicates the 5-HT7 receptor in a variety of functions
and pathologies. This idea is reinforced by the fact that several
therapeutic agents, such as tricyclic antidepressants, typical and
atypical antipsychotics and some 5-HT2 receptor antagonists, display
moderate to high affinity for both recombinant and functional 5-HT7
receptors.

[0004]Functionally, the 5-HT7 receptor has been implicated in
regulation of circadian rhythms in mammals (Lovenberg, T. W. et al.
Neuron, 1993, 11:449-458 "A novel adenylyl cyclase-activating serotonin
receptor (5-HT7) implicated in the regulation of circadian
rhythms"). It is known that disruption of circadian rhythms is related to
a number of CNS disorders including depression, seasonal affective
disorder, sleep disorders, shift worker syndrome and jet lag among
others.

[0005]Distribution and early pharmacological data also suggest that the
5-HT7 receptor is involved in the vasodilatation of blood vessels.
This has been demonstrated in vivo (Terron, J. A., Br J Pharmacol, 1997,
121:563-571 "Role of 5-HT7 receptors in the long lasting hypotensive
response induced by 5-hydroxytryptamine in the rat"). Thus selective
5-HT7 receptor agonists have a potential as novel hypertensive
agents.

[0007]In view of the potential therapeutic applications of agonists or
antagonists of the 5HT7 receptor, a great effort has been directed
to find selective ligands. Despite intense research efforts in this area,
very few compounds with selective 5-HT7 antagonist activity have
been reported (Wesolowska, A., Polish J. Pharmacol., 2002, 54: 327-341,
"In the search for selective ligands of 5-HT5, 5-HT5 and
5-HT7 serotonin receptors"), yet even fewer 5-HT7-Agonists.

[0008]There is still a need to find compounds that have pharmacological
activity towards the receptor 5-HT7, being both effective and
selective, and having good "drugability" properties, i.e. good
pharmaceutical properties related to administration, distribution,
metabolism and excretion.

[0009]Thus, it was an object of the present invention to provide novel
compounds that are suitable in particular as active substances in
medicaments.

[0010]Said object was achieved by providing a
heterocyclyl-substituted-ethylamino-phenyl derivative of general formula
(I)

##STR00001##

wherein

[0011]K-L-M-N together form [0012]═CH--X--Y═CH--; in which any
suitable H may be substituted by R6 and/or R7, and in which X
is selected from NR8, O or S, while Y is selected from N or CH;
[0013]═CH--X--Y--C(O)--; in which any suitable H may be substituted
by R6 and in which one of X and Y is NR8, while the other is
selected from NR8a, S or O; [0014]═CH--X--Y--C(O)--; in which
one of X and Y is CH2, while the other is selected from NR8, S
or O, in which any suitable H may be substituted by R6 and/or
R7; [0015]═CR6--N═N--C(O)--;
[0016]═CR9--CH═CH--CH═CH--; in which any suitable H may
be substituted by R6;
[0017]═CR9--CH═CH--CH═CR9a--; in which any suitable
H may be substituted by R6; [0018]═CH--X═Y--CH═CH--; in
which any suitable H may be substituted by R6 and/or R7, and in
which one of X or Y is selected from N, while the other is selected from
N or CH; [0019]═CH--X═Y--CH2--CH2--; in which any
suitable H may be substituted by R6 and/or R7, and in which one
of X or Y is selected from N, while the other is selected from N or CH;
[0020]═CH--X--Y--CH═CH--; in which any suitable H may be
substituted by R6 and/or R7, and in which one of X or Y is
selected from NR8, O or S while the other is selected from NR8a
or CH2; [0021]═CH--X--Y--CH2--CH2--; in which any
suitable H may be substituted by R6 and/or R7, and in which one
of X or Y is selected from NR8, O or S while the other is selected
from NR8a or CH2; [0022]═CH--X--CH2--Y═CH--; in
which any suitable H may be substituted by R6 and/or R7, and in
which X is selected from NR8, O or S while Y is selected from N or
CH; [0023]═CH--X--CH═Y--CH2--; in which any suitable H may
be substituted by R6 and/or R7, and in which X is selected from
NR8, O or S while Y is selected from N or CH;
[0024]═CH--N═CH--Y═CH--; in which any suitable H may be
substituted by R6 and/or R7;
[0025]═CH--X--CH2--Y--CH2--; in which any suitable H may be
substituted by R6 and/or R7, and in which one of X or Y is
selected from NR8, O or S while the other is selected from
NR8a, O, S or CH2;

[0026]R1 and R2 each are independently selected from the group
consisting of hydrogen; or a linear or branched, saturated or
unsaturated, optionally at least mono-substituted aliphatic radical; or

[0027]R1 and R2 together with the bridging nitrogen atom form an
saturated or unsaturated, optionally at least mono-substituted 5- or
6-membered-heterocyclic ring, which may be condensed with an optionally
at least mono-substituted mono- or polycyclic ringsystem;

[0028]Z is selected from [0029]--(CH2)n--, with n being 1, 2,
3 or 4; [0030]--O--(CH2)n--, with n being 1, 2, 3 or 4;
[0031]--S--(CH2)n--, with n being 1, 2, 3 or 4;
[0032](CH2)n--(CHR5)--(CH2)m, with n and m being
selected from 0, 1, 2 or 3 and m+n being 1, 2 or 3, with R5 being
selected from F, Cl, Br, I, OH, SH, or unsubstituted C1-4-Alkyl;

[0033]R3 and R4 are independently from each other selected from
hydrogen; halogen, OH, SH, NH2; a linear or branched, saturated or
unsaturated, optionally at least mono-substituted aliphatic radical; or
O--R with R being a linear or branched, saturated or unsaturated,
optionally at least mono-substituted aliphatic radical;

[0034]R6 and R7 are independently from each other selected from
hydrogen; halogen, OH, SH, NH2; an aliphatic radical, which is
linear or branched, saturated or unsaturated, and optionally at least
mono-substituted by F, Cl, Br, I, SH or OH; or O--R with R being an
aliphatic radical, which is linear or branched, saturated or unsaturated,
and optionally at least mono-substituted by F, Cl, Br, I, SH or OH;

[0035]R8 and R8a are independently from each other selected from
hydrogen; or an aliphatic radical, which is linear or branched, saturated
or unsaturated, and optionally at least mono-substituted by F, Cl, Br, I,
SH or OH;

[0036]R9 and R9a are independently from each other selected from
an aliphatic radical, which is linear or branched, saturated or
unsaturated, and optionally at least mono-substituted by F, Cl, Br, I, SH
or OH; or O--R with R being an aliphatic radical, which is linear or
branched, saturated or unsaturated, and optionally at least
mono-substituted by F, Cl, Br, I, SH or OH; or R9 and R9a both
are identical and selected from F, or Cl;

[0037]preferably R9 and R9a are independently from each other
selected from an aliphatic radical, which is linear or branched,
saturated or unsaturated, and optionally at least mono-substituted by F,
Cl, Br, I, SH or OH; or O--R with R being an aliphatic radical, which is
linear or branched, saturated or unsaturated, and optionally at least
mono-substituted by F, Cl, Br, I, SH or OH;

[0038]optionally in form of one of its stereoisomers, preferably
enantiomers or diastereomers, its racemate or in form of a mixture of at
least two of its stereoisomers, preferably enantiomers or diastereomers,
in any mixing ratio; in form of a salt, preferably a physiologically
acceptable salt thereof, or a corresponding solvate, or N-oxide
respectively.

[0039]In a preferred embodiment the following proviso(s)/disclaimer(s)
applies: [0040]with the proviso that [0041]if R1 and R2 are
both CH3, R3 and R4 are both H, K-L-M-N together form
═CR9--CH═CH--CH═CR9a-- and one of R9 or
R9a is --CH═CH2, the other may not be OCH3;and/or
[0042]with the proviso that if R1 and R2 are both H, one of
R3 and R4 is H, while the other is --O(C2H5), K-L-M-N
together form ═CR9--CR6═CH--CH═CH--, and R9 is
--OCH3, R6 may not be OCH3.

[0043]These compounds show a high affinity to the 5HT7 Receptor as
well as a high selectivity for this receptor in comparison to e.g. the
5HT6, the Sigma 1, the α2, and the 5HT1 Receptor, thus
having a higher affinity to the 5HT7 receptor. In addition some of
these compounds show an agonistic activity on this receptor.

[0044]A "mono- or polycyclic ring-system" according to the present
invention means a mono- or polycyclic hydrocarbon ring-system that may be
saturated, unsaturated or aromatic. If the ring system is polycyclic,
each of its different rings may show a different degree of saturation,
i.e. it may be saturated, unsaturated or aromatic. Optionally each of the
rings of the mono- or polycyclic ring system may contain one or more
heteroatoms as ring members, which may be identical or different and
which can preferably be selected from the group consisting of N, O, S and
P, more preferably be selected from the group consisting of N, O and S.
Preferably the polycyclic ring-system may comprise two rings that are
condensed. The rings of the mono- or polycyclic ring-system are
preferably 5- or 6-membered.

[0045]An "aryl", "aryl radical" or group is understood as meaning ring
systems with at least one aromatic ring but without heteroatoms even in
only one of the rings. Examples are phenyl, naphthyl, fluoranthenyl,
fluorenyl, tetralinyl or indanyl, in particular 9H-fluorenyl or
anthracenyl radicals, which can be unsubstituted or monosubstituted or
polysubstituted.

[0046]In the context of this invention "cycloalkyl radical" or group is
understood as meaning saturated and unsaturated (but not aromatic) cyclic
hydrocarbons (without a heteroatom in the ring), which can be
unsubstituted or mono- or polysubstituted. Furthermore,
C3-4-cycloalkyl represents C3- or C4-cycloalkyl,
C3-5-cycloalkyl represents C3-, C4- or C5-cycloalkyl,
C3-6-cycloalkyl represents C3-, C4-, C5- or
C6-cycloalkyl, C3-7-cycloalkyl represents C3-, C4-,
C5-, C6- or C7-cycloalkyl, C3-8-cycloalkyl represents
C3-, C4-, C5-, C6-, C7- or C8-cycloalkyl,
C4-5-cycloalkyl represents C4- or C5-cycloalkyl,
C4-6-cycloalkyl represents C4-, C5- or C6-cycloalkyl,
C4-7-cycloalkyl represents C4-, C5-, C6- or
C7-cycloalkyl, C4-8-cycloalkyl represents C4-, C5,
C6- C7- or C8-cycloalkyl C5-6-cycloalkyl represents
C5- or C6-cycloalkyl and C5-7-cycloalkyl represents
C5-, C6- or C7cycloalkyl. However, mono- or
polyunsaturated, preferably monounsaturated, cycloalkyls also in
particular fall under the term cycloalkyl as long as the cycloalkyl is
not an aromatic system. The cycloalkyl radicals are preferably
cyclopropyl, 2-methylcyclopropyl, cyclopropylmethyl, cyclobutyl,
cyclopentyl, cyclopentylmethyl, cyclohexyl, cycloheptyl, cyclooctyl, and
also adamantly.

[0047]A "heterocyclyl", a "heterocyclyl radical" or group or "heterocyclic
ring system" is understood as meaning heterocyclic ring systems which
contain one or more heteroatoms from the group consisting of nitrogen,
oxygen and/or sulfur in the ring or ringsystem, and can also be mono- or
polysubstituted. The ringsystem may consist either of only one saturated
or unsaturated or even aromatic ring or may consist of 2, 3 or 4
saturated or unsaturated or even aromatic rings, which are condensed in
that between two or more of the rings ring members are shared. Examples
which may be mentioned from the group of heterocyclyls are furan,
benzofuran, thiophene, benzothiophene, pyrrole, pyridine, pyrimidine,
pyrazine, quinoline, isoquinoline, phthalazine, benzo-1,2,5-thiadiazole,
imidazo-thiazole, benzothiazole, indole, benzotriazole, benzodioxolane,
benzodioxane, carbazole and quinazoline.

[0048]In connection with mono- or polycyclic ring-system, aryl radical,
cycloalkyl radical, or heterocyclyl radical, "substituted" is understood
- unless defined otherwise - as meaning replacement of at least one
hydrogen radical on the ring-system of the mono- or polycyclic
ring-system, the aryl radical, the cycloalkyl radical, or the
heterocyclyl radical by OH, SH, ═O, halogen (F, Cl, Br, I), CN,
NO2, COOH; NRxRy, with Rx and Ry independently
being either H or a saturated or unsaturated, linear or branched,
substituted or unsubstituted C1-6-alkyl; by a saturated or
unsaturated, linear or branched, substituted or unsubstituted
C1-6-alkyl; a saturated or unsaturated, linear or branched,
substituted or unsubstituted (alkoxy); a saturated or unsaturated, linear
or branched, substituted or unsubstituted --S--C1-6-alkyl; a
saturated or unsaturated, linear or branched, substituted or
unsubstituted --C(O--C1-6-alkyl; a saturated or unsaturated, linear
or branched, substituted or unsubstituted --C(O)--O--C1-6alkyl; a
substituted or unsubstituted phenyl. Within that "monosubstituted" means
the substitution of exactly one hydrogen radical, whereas
"polysubstituted" means the substitution of more than one hydrogen
radical with "polysubstituted"radicals being understood as meaning that
the replacement takes effect both on different and on the same atoms
several times with the same or different substituents. Therefore,
"optionally at least monsubstituted" means either "not substituted" if
the option is not fulfilled, "monosubstituted" or "polysubstituted".

[0049]In connection with aryl radical, cycloalkyl radical, or heterocyclyl
radical, "condensed with" is understood as meaning that the ring-system
of the aryl radical, the cycloalkyl radical, or the heterocyclyl radical
is sharing two atoms (one) of its ring(s) with a ring of the mono- or
polycyclic ring-system it is condensed with.

[0050]Aliphatic radicals/groups, as referred to in the present invention,
are optionally mono- or polysubstituted and may be branched or linear,
saturated or unsaturated. Aliphatic radicals, as defined in the present
invention, include alkyl, alkenyl and alkinyl radicals. Unsaturated
aliphatic radicals, as defined in the present invention, include alkenyl
and alkinyl radicals. Preferred aliphatic radicals according to the
present invention include but are not restricted to methyl, ethyl, vinyl
(ethenyl), ethinyl, propyl, n-propyl, isopropyl, allyl (2-propenyl),
1-propinyl, methylethyl, butyl, n-butyl, iso-butyl, sec-butyl, tert-butyl
butenyl, butinyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl,
pentyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl,
2,2-dimethylpropyl, hexyl, 1-methylpentyl, n-heptyl, n-octyl, n-nonyl and
n-decyl.

[0052]In connection with alkylene, alkyl or aliphatic radical or
group--unless defined otherwise--the term "substituted" in the context of
this invention is understood as meaning replacement of at least one
hydrogen radical by F, Cl, Br, I, NH2, SH or OH; within that
"monosubstituted" means the substitution of exactly one hydrogen radical,
whereas "polysubstituted" means the substitution of more than one
hydrogen radical with "polysubstituted"radicals being understood as
meaning that the replacement takes effect both on different and on the
same atoms several times with the same or different substituents, for
example three times on the same C atom, as in the case of CF3, or at
different places, as in the case of e.g. --CH(OH)--CH═CH--CHCl2.
Therefore, "optionally at least monsubstituted" means either "not
substituted" if the option is not fulfilled, "monosubstituted" or
"polysubstituted".

[0053]The term "alkylene" is understood as meaning a divalent alkyl group
like --CH2-- or --CH2--CH2--, with (CH2)3-6
being understood as meaning --CH2--CH2--CH2--,
--CH2--CH2--CH2--CH2--,
--CH2--CH2--CH2--CH2--CH2-- and
--CH2--CH2--CH2--CH2--CH2--CH2--,
(CH2)1-4 is to be understood as meaning --CH2--,
--CH2--CH2--, --CH2--CH2--CH2-- and
--CH2--CH2--CH2--CH2--, (CH2)4-5 is to be
understood as meaning --CH2--CH2--CH2--CH2-- and
--CH2--CH2--CH2--CH2--CH2--, etc. An "alkylene"
may also be unsaturated.

[0054]The term "salt" is to be understood as meaning any form of the
active compound used according to the invention in which it assumes an
ionic form or is charged and is coupled with a counter-ion (a cation or
anion) or is in solution. By this are also to be understood complexes of
the active compound with other molecules and ions, in particular
complexes which are complexed via ionic interactions.

[0055]The term "physiologically acceptable salt" means in the context of
this invention any salt that is physiologically tolerated (most of the
time meaning not being toxic-especially not caused by the counter-ion) if
used appropriately for a treatment especially if used on or applied to
humans and/or mammals.

[0056]These physiologically acceptable salts can be formed with cations or
bases and in the context of this invention is understood as meaning salts
of at least one of the compounds used according to the invention--usually
a (deprotonated) acid--as an anion with at least one, preferably
inorganic, cation which is physiologically tolerated--especially if used
on humans and/or mammals. The salts of the alkali metals and alkaline
earth metals are particularly preferred, and also those with NH4, but in
particular (mono)- or (di)sodium, (mono)- or (di)potassium, magnesium or
calcium salts.

[0057]These physiologically acceptable salts can also be formed with
anions or acids in the context of this invention is understood as meaning
salts of at least one of the compounds used according to the
invention--usually protonated, for example on the nitrogen--as the cation
with at least one anion which are physiologically tolerated--especially
if used on humans and/or mammals. By this is understood in particular, in
the context of this invention, the salt formed with a physiologically
tolerated acid, that is to say salts of the particular active compound
with inorganic or organic acids which are physiologically tolerated -
especially if used on humans and/or mammals. Examples of physiologically
tolerated salts of particular acids are salts of: hydrochloric acid,
hydrobromic acid, sulfuric acid, methanesulfonic acid, formic acid,
acetic acid, oxalic acid, succinic acid, malic acid, tartaric acid,
mandelic acid, fumaric acid, lactic acid or citric acid.

[0058]The compounds of the invention may be in crystalline form or either
as free compounds or as solvates and it is intended that those forms are
within the scope of the present invention. Methods of solvation are
generally known within the art. Suitable solvates are pharmaceutically
acceptable solvates. The term "solvate" according to this invention is to
be understood as meaning any form of the active compound according to the
invention in which this compound has attached to it via non-covalent
binding another molecule (most likely a polar solvent) especially
including hydrates and alcoholates, e.g. methanolate.

[0059]Unless otherwise stated, the compounds of the invention are also
meant to include compounds which differ only in the presence of one or
more isotopically enriched atoms. For example, compounds having the
present structures except for the replacement of a hydrogen by a
deuterium or tritium, or the replacement of a carbon by 13C- or
14C-enriched carbon or 15N-enriched nitrogen are within the
scope of this invention.

[0060]Any compound that is a prodrug of a compound of formula (I) is
within the scope of the invention. The term "prodrug" is used in its
broadest sense and encompasses those derivatives that are converted in
vivo to the compounds of the invention. Such derivatives would readily
occur to those skilled in the art, and include, depending on the
functional groups present in the molecule and without limitation, the
following derivatives of the present compounds: esters, amino acid
esters, phosphate esters, metal salts sulfonate esters, carbamates, and
amides. Examples of well known methods of producing a prodrug of a given
acting compound are known to those skilled in the art and can be found
e.g. in Krogsgaard-Larsen et al. "Textbook of Drug design and Discovery"
Taylor & Francis (April 2002).

[0061]The compounds of formula (I) or their salts or solvates are
preferably in pharmaceutically acceptable or substantially pure form. By
pharmaceutically acceptable form is meant, inter alia, having a
pharmaceutically acceptable level of purity excluding normal
pharmaceutical additives such as diluents and carriers, and including no
material considered toxic at normal dosage levels. Purity levels for the
drug substance are preferably above 50%, more preferably above 70%, most
preferably above 90%. In a preferred embodiment it is above 95% of the
compound of formula (I) or, or of its salts, solvates or prodrugs.

[0062]Particularly preferred are compounds according to the invention
which are compounds of general formula (Ia),

##STR00002##

wherein

[0063]A is a compound selected from the following group

##STR00003##

[0064]preferably

##STR00004##

[0065]R1 and R2 each are independently selected from the group
consisting of hydrogen; or a linear or branched, saturated or
unsaturated, optionally at least mono-substituted aliphatic radical; or

[0066]R1 and R2 together with the bridging nitrogen atom form an
saturated or unsaturated, optionally at least mono-substituted 5- or
6-membered-heterocyclic ring, which may be condensed with an optionally
at least mono-substituted mono- or polycyclic ringsystem,

[0067]R3 and R4 are independently from each other selected from
hydrogen; halogen, OH, SH, NH2; a linear or branched, saturated or
unsaturated, optionally at least mono-substituted aliphatic radical; or
O--R with R being a linear or branched, saturated or unsaturated,
optionally at least mono-substituted aliphatic radical;

[0068]R6 and R7 are independently from each other selected from
hydrogen; halogen, OH, SH, NH2; an aliphatic radical, which is
linear or branched, saturated or unsaturated, and optionally at least
mono-substituted by F, Cl, Br, I, SH or OH; or O--R with R being an
aliphatic radical, which is linear or branched, saturated or unsaturated,
and optionally at least mono-substituted by F, Cl, Br, I, SH or OH;

[0069]R8 and R8a are independently from each other selected from
hydrogen; or an aliphatic radical, which is linear or branched, saturated
or unsaturated, and optionally at least mono-substituted by F, Cl, Br, I,
SH or OH;

[0070]R9 and R9a are independently from each other selected from
an aliphatic radical, which is linear or branched, saturated or
unsaturated, and optionally at least mono-substituted by F, Cl, Br, I, SH
or OH; or O--R with R being an aliphatic radical, which is linear or
branched, saturated or unsaturated, and optionally at least
mono-substituted by F, Cl, Br, I, SH or OH; or R9 and R9a both
are identical and selected from F, or Cl;

[0071]preferably R9 and R9a are independently from each other
selected from an aliphatic radical, which is linear or branched,
saturated or unsaturated, and optionally at least mono-substituted by F,
Cl, Br, I, SH or OH; or O--R with R being an aliphatic radical, which is
linear or branched, saturated or unsaturated, and optionally at least
mono-substituted by F, Cl, Br, I, SH or OH.

In a preferred embodiment the following proviso(s)/disclaimer(s) applies:

[0072]with the proviso that

[0073]if R1 and R2 are both CH3, R3 and R4 are
both H, A is

##STR00005##

[0074]and one of R9 or R9a is --CH═CH2, the other may
not be OCH3;

and/or

[0075]with the proviso that

[0076]if R1 and R2 are both H, one of R3 and R4 is H,
while the other is --O(C2H5), A is

##STR00006##

[0077]and R9 is --OCH3, R6 may not be OCH3 in the
position marked with "*".

Also particularly preferred is a compound according to the invention,
which is a compound according to Formula Ia, wherein

[0078]A is a compound selected from the following group

##STR00007##

preferably

##STR00008##

[0079]R1 and R2 each are independently selected from the group
consisting of hydrogen; or a linear or branched, saturated or
unsaturated, optionally at least mono-substituted aliphatic radical; or

[0080]R1 and R2 together with the bridging nitrogen atom form an
saturated or unsaturated, optionally at least mono-substituted 5- or
6-membered-heterocyclic ring, which may be condensed with an optionally
at least mono-substituted mono- or polycyclic ringsystem,

[0081]R3 and R4 are independently from each other selected from
hydrogen; halogen, OH, SH, NH2; a linear or branched, saturated or
unsaturated, optionally at least mono-substituted aliphatic radical; or
O--R with R being a linear or branched, saturated or unsaturated,
optionally at least mono-substituted aliphatic radical;

[0082]R6 and R7 are independently from each other selected from
hydrogen; halogen, OH, SH, NH2; an aliphatic radical, which is
linear or branched, saturated or unsaturated, and optionally at least
mono-substituted by F, Cl, Br, I, SH or OH; or O--R with R being an
aliphatic radical, which is linear or branched, saturated or unsaturated,
and optionally at least mono-substituted by F, Cl, Br, I, SH or OH;

[0083]R8 and R8a are independently from each other selected from
hydrogen; or an aliphatic radical, which is linear or branched, saturated
or unsaturated, and optionally at least mono-substituted by F, Cl, Br, I,
SH or OH;

[0084]R9 and R9a are independently from each other selected from
an aliphatic radical, which is linear or branched, saturated or
unsaturated, and optionally at least mono-substituted by F, Cl, Br, I, SH
or OH; or O--R with R being an aliphatic radical, which is linear or
branched, saturated or unsaturated, and optionally at least
mono-substituted by F, Cl, Br, I, SH or OH; or R9 and R9a both
are identical and selected from F, or Cl;

[0085]preferably R9 and R9a are independently from each other
selected from an aliphatic radical, which is linear or branched,
saturated or unsaturated, and optionally at least mono-substituted by F,
Cl, Br, I, SH or OH; or O--R with R being an aliphatic radical, which is
linear or branched, saturated or unsaturated, and optionally at least
mono-substituted by F, Cl, Br, I, SH or OH.

In a preferred embodiment the following proviso(s)/disclaimer(s) applies:

[0086]with the proviso that

[0087]if R1 and R2 are both CH3, R3 and R4 are
both H, A is

##STR00009##

[0088]and one of R9 or R9a is --CH═CH2, the other may
not be OCH3;

and/or

[0089]with the proviso that

[0090]if R1 and R2 are both H, one of R3 and R4 is H,
while the other is --O(C2H5), A is

##STR00010##

[0091]and R9 is --OCH3, R6 may not be OCH3 in the
position marked with "*".

Also particularly preferred is a compound according to the invention,
which is a compound according to Formula Ia, wherein

[0092]A is a compound selected from the following group

##STR00011##

[0093]preferably

##STR00012##

[0094]R1 and R2 each are independently selected from the group
consisting of hydrogen; or a linear or branched, saturated or
unsaturated, optionally at least mono-substituted aliphatic radical; or

[0095]R1 and R2 together with the bridging nitrogen atom form an
saturated or unsaturated, optionally at least mono-substituted 5- or
6-membered-heterocyclic ring, which may be condensed with an optionally
at least mono-substituted mono- or polycyclic ringsystem,

[0096]R3 and R4 are independently from each other selected from
hydrogen; halogen, OH, SH, NH2; a linear or branched, saturated or
unsaturated, optionally at least mono-substituted aliphatic radical; or
O--R with R being a linear or branched, saturated or unsaturated,
optionally at least mono-substituted aliphatic radical;

[0097]R6 and R7 are independently from each other selected from
hydrogen; halogen, OH, SH, NH2; an aliphatic radical, which is
linear or branched, saturated or unsaturated, and optionally at least
mono-substituted by F, Cl, Br, I, SH or OH; or O--R with R being an
aliphatic radical, which is linear or branched, saturated or unsaturated,
and optionally at least mono-substituted by F, Cl, Br, I, SH or OH;

[0098]R8 and R8a are independently from each other selected from
hydrogen; or an aliphatic radical, which is linear or branched, saturated
or unsaturated, and optionally at least mono-substituted by F, Cl, Br, I,
SH or OH;

[0099]R9 and R9a are independently from each other selected from
an aliphatic radical, which is linear or branched, saturated or
unsaturated, and optionally at least mono-substituted by F, Cl, Br, I, SH
or OH; or O--R with R being an aliphatic radical, which is linear or
branched, saturated or unsaturated, and optionally at least
mono-substituted by F, Cl, Br, I, SH or OH; or R9 and R9a both
are identical and selected from F, or Cl;

[0100]preferably R9 and R9a are independently from each other
selected from an aliphatic radical, which is linear or branched,
saturated or unsaturated, and optionally at least mono-substituted by F,
Cl, Br, I, SH or OH; or O--R with R being an aliphatic radical, which is
linear or branched, saturated or unsaturated, and optionally at least
mono-substituted by F, Cl, Br, I, SH or OH;

In a preferred embodiment the following proviso(s)/disclaimer(s) applies:

[0101]with the proviso that

[0102]if R1 and R2 are both CH3, R3 and R4 are
both H, A is

##STR00013##

[0103]and one of R9 orR9a is --CH═CH2, the other may
not be OCH3;

and/or

[0104]with the proviso that

[0105]if R1 and R2 are both H, one of R3 and R4 is H,
while the other is --O(C2H5), A is

##STR00014##

[0106]and R9 is --OCH3, R6 may not be OCH3 in the
position marked with "*".

Also particularly preferred is a compound according to the invention,
which is a compound of GROUP A according to Formula Ia, wherein

[0107]A is a compound selected from the following group

##STR00015##

[0108]R1 and R2 each are independently selected from the group
consisting of hydrogen; or a linear or branched, saturated or
unsaturated, optionally at least mono-substituted aliphatic radical; or

[0109]R1 and R2 together with the bridging nitrogen atom form an
saturated or unsaturated, optionally at least mono-substituted 5- or
6-membered-heterocyclic ring, which may be condensed with an optionally
at least mono-substituted mono- or polycyclic ringsystem;

[0110]R3 and R4 are independently from each other selected from
hydrogen; halogen, OH, SH, NH2; a linear or branched, saturated or
unsaturated, optionally at least mono-substituted aliphatic radical; or
O--R with R being a linear or branched, saturated or unsaturated,
optionally at least mono-substituted aliphatic radical;

[0111]R6 and R7 are independently from each other selected from
hydrogen; halogen, OH, SH, NH2; an aliphatic radical, which is
linear or branched, saturated or unsaturated, and optionally at least
mono-substituted by F, Cl, Br, I, SH or OH; or O--R with R being an
aliphatic radical, which is linear or branched, saturated or unsaturated,
and optionally at least mono-substituted by F, Cl, Br, I, SH or OH;

[0112]R8 is selected from hydrogen; or an aliphatic radical, which is
linear or branched, saturated or unsaturated, and optionally at least
mono-substituted by F, Cl, Br, I, SH or OH.

Also particularly preferred is a compound according to the invention,
which is a compound of GROUP B according to Formula Ia, wherein

[0113]A is a compound selected from the following group

##STR00016##

[0114]preferably

##STR00017##

[0115]R1 and R2 each are independently selected from the group
consisting of hydrogen; or a linear or branched, saturated or
unsaturated, optionally at least mono-substituted aliphatic radical; or

[0116]R1 and R2 together with the bridging nitrogen atom form an
saturated or unsaturated, optionally at least mono-substituted 5- or
6-membered-heterocyclic ring, which may be condensed with an optionally
at least mono-substituted mono- or polycyclic ringsystem,

[0117]R3 and R4 are independently from each other selected from
hydrogen; halogen, OH, SH, NH2; a linear or branched, saturated or
unsaturated, optionally at least mono-substituted aliphatic radical; or
O--R with R being a linear or branched, saturated or unsaturated,
optionally at least mono-substituted aliphatic radical;

[0118]R6 is selected from hydrogen; halogen, OH, SH, NH2; an
aliphatic radical, which is linear or branched, saturated or unsaturated,
and optionally at least mono-substituted by F, Cl, Br, I, SH or OH; or
O--R with R being an aliphatic radical, which is linear or branched,
saturated or unsaturated, and optionally at least mono-substituted by F,
Cl, Br, I, SH or OH;

[0119]R9 and R9a are independently from each other selected from
an aliphatic radical, which is linear or branched, saturated or
unsaturated, and optionally at least mono-substituted by F, Cl, Br, I, SH
or OH; or O--R with R being an aliphatic radical, which is linear or
branched, saturated or unsaturated, and optionally at least
mono-substituted by F, Cl, Br, I, SH or OH; or R9 and R9a both
are identical and selected from F, or Cl;

[0120]preferably R9 and R9a are independently from each other
selected from an aliphatic radical, which is linear or branched,
saturated or unsaturated, and optionally at least mono-substituted by F,
Cl, Br, I, SH or OH; or O--R with R being an aliphatic radical, which is
linear or branched, saturated or unsaturated, and optionally at least
mono-substituted by F, Cl, Br, I, SH or OH.

In a preferred embodiment the following proviso(s)/disclaimer(s) applies
for GROUP B:

[0121]with the proviso that [0122]if R1 and R2 are both
CH3, R3 and R4 are both H, A is

##STR00018##

[0123]and one of R9 or R9a is --CH═CH2, the other may
not be OCH3;

and/or

[0124]with the proviso that

[0125]if R1 and R2 are both H, one of R3 and R4 is H,
while the other is --O(C2H5), A is

##STR00019##

and R9 is --OCH3, R6 may not be OCH3 in the position
marked with "*".Also particularly preferred is a compound according to
the invention, which is a compound of GROUP A according to Formula Ia,
wherein

[0126]R1 and R2 each are independently selected from the group
consisting of hydrogen; or a linear or branched, optionally at least
mono-substituted C1-4-alkyl radical; or

[0127]R1 and R2 together with the bridging nitrogen atom form an
saturated or unsaturated, optionally at least mono-substituted 5- or
6-membered-heterocyclic ring;

[0128]preferably in that

[0129]R1 and R2 are each independently selected from the group
consisting of hydrogen; or a linear or branched C1-4-alkyl radical;
or

[0130]R1 and R2 together with the bridging nitrogen atom form an
saturated or unsaturated, optionally at least mono-substituted 5- or
6-membered-heterocyclic ring;

[0131]more preferably in that

[0132]R1 and R2 are each independently selected from the group
consisting of hydrogen, CH3, C2H5, C3H7, or
C4H9; or

[0133]R1 and R2 together with the bridging nitrogen atom form an
saturated or unsaturated, optionally at least mono-substituted 5- or
6-membered-heterocyclic ring, selected from piperidine and pyrazole;;

[0134]most preferably in that

[0135]R1 and R2 are each independently selected from the group
consisting of hydrogen, CH3, C2H5 or C3H7.

Also particularly preferred is a compound according to the invention,
which is a compound of GROUP A according to Formula Ia, wherein

[0136]R3 and R4 are independently from each other selected from
hydrogen; halogen, OH, SH, NH2; a linear or branched, optionally at
least mono-substituted C1-4-alkyl radical; or O--R with R being a
linear or branched, optionally at least mono-substituted C1-4-alkyl
radical;

Also particularly preferred is a compound according to the invention,
which is a compound of GROUP A according to Formula Ia, wherein

[0143]R6 and R7 are independently from each other selected from
hydrogen; halogen, OH, SH, NH2; a C1-4-alkyl radical, which is
linear or branched, and optionally at least mono-substituted by F, Cl,
Br, I, SH or OH; or O--R with R being a C1-4-alkyl radical, which is
linear or branched, and optionally at least mono-substituted by F, Cl,
Br, I, SH or OH;

[0185]optionally in form of a salt, preferably a physiologically
acceptable salt, more preferably in form of a physiologically acceptable
acid addition salt, most preferably a hydrochloride salt, or a
corresponding solvate or N-oxide.

Also particularly preferred is a compound according to the invention,
which is a compound of GROUP A according to Formula Ia, selected from
[0186]Dimethyl-{2-[3-(1,3,5-trimethyl-1H-pyrazol-4-yl)-phenyl]-ethyl}-ami-
ne, [0187]Methyl-{2-[3-(1,3,5-trimethyl-1H-pyrazol-4-yl)-phenyl]-ethyl}-am-
ine, [0188]Diethyl-{2-[3-(1,3,5-trimethyl-1H-pyrazol-4-yl)-phenyl]-ethyl}--
amine, [0189]Dipropyl-{2-[3-(1,3,5-trimethyl-1H-pyrazol-4-yl)-phenyl]-ethy-
l}-amine, [0190]{2-[3-(3,5-Dimethyl-1H-pyrazol-4-yl)-phenyl]-ethyl}-dimeth-
yl-amine, [0191]{2-[3-(3,5-Dimethyl-1H-pyrazol-4-yl)-phenyl]-ethyl}-methyl-
-amine, [0192]{2-[3-(3,5-Dimethyl-1H-pyrazol-4-yl)-phenyl]-ethyl}-diethyl--
amine, [0193]{2-[3-(3,5-Dimethyl-1H-pyrazol-4-yl)-phenyl]-ethyl}-dipropyl--
amine, [0194]Dimethyl-{2-[3-(1-methyl-1H-pyrazol-4-yl)-phenyl]-ethyl}-amin-
e, [0195]Methyl-{2-[3-(1-methyl-1H-pyrazol-4-yl)-phenyl]-ethyl}-amine,
[0196]Diethyl-{2-[3-(1-methyl-1H-pyrazol-4-yl)-phenyl]-ethyl}-amine,
[0197]{2-[3-(1-Methyl-1H-pyrazol-4-yl)phenyl]-ethyl}-dipropyl-amine,
[0198]{2-[3-(3,5-Dimethyl-isoxazol-4-yl)-phenyl]-ethyl}-dimethyl-amine,
[0199]{2-[3-(3,5-Dimethyl-isoxazol-4-yl)-phenyl]-ethyl}-methyl-amine,
[0200]{2-[3-(3,5-Dimethyl-isoxazol-4-yl)-phenyl]-ethyl}-diethyl-amine,
[0201]{2-[3-(3,5-Dimethyl-isoxazol-4-yl)-phenyl]-ethyl}-dipropyl-amine,

[0202]optionally in form of a salt, preferably a physiologically
acceptable salt, more preferably in form of a physiologically acceptable
acid addition salt, most preferably a hydrochloride salt, or a
corresponding solvate.

Also particularly preferred is a compound according to the invention,
which is a compound of GROUP B according to Formula Ia, wherein

[0203]R6 is selected from hydrogen; halogen, OH, SH, NH2; a
C1-4-alkyl radical, which is linear or branched, and optionally at
least mono-substituted by F, Cl, Br, I, SH or OH; or O--R with R being a
C1-4-alkyl radical, which is linear or branched, and optionally at
least mono-substituted by F, Cl, Br, I, SH or OH;

Also particularly preferred is a compound according to the invention,
which is a compound of GROUP B according to Formula Ia, wherein

[0210]R9 and R9a are independently from each other selected from
a C1-4-alkyl radical, which is linear or branched, and optionally at
least mono-substituted by F, Cl, Br, I, SH or OH; or O--R with R being a
C1-4-alkyl radical, which is linear or branched, and optionally at
least mono-substituted by F, Cl, Br, I, SH or OH;

[0211]preferably in that

[0212]R9 and R9a are independently from each other selected from
CH3, C2H5, C3H7, C4H9, OCH3,
OC2H5, OC3H7 or OC4H9;

[0213]more preferably in that

[0214]R9 and R9a are independently from each other selected from
CH3, or OCH3.

[0215]most preferably in that

[0216]R9 and R9a are both selected either from CH3, or
OCH3.

[0217]Also particularly preferred is a compound according to the
invention, which is a compound of GROUP B according to Formula Ia,
wherein

[0218]R9 and R9a are independently from each other selected from
a C1-4-alkyl radical, which is linear or branched, and optionally at
least mono-substituted by F, Cl, Br, I, SH or OH; or O--R with R being a
C1-4-alkyl radical, which is linear or branched, and optionally at
least mono-substituted by F, Cl, Br, I, SH or OH; or R9 and R9a
both are identical and selected from F, or Cl;

[0219]preferably in that

[0220]R9 and R9a are independently from each other selected from
CH3, C2H5, C3H7, C4H9, OCH3,
OC2H5, OC3H7 or OC4H9; or R9 and
R9a both are identical and selected from F, F, or Cl;

[0221]more preferably in that

[0222]R9 and R9a are independently from each other selected from
CH3, or OCH3; or R9 and R9a both are identical and
selected from F, or Cl;

[0223]most preferably in that

[0224]R9 and R9a are both selected either from CH3,
OCH3, F, or Cl.

Also particularly preferred is a compound according to the invention,
which is a compound of GROUP B according to Formula Ia selected from
[0225][2-(2',6'-Dimethyl-biphenyl-3-yl)-ethyl]-dimethyl-amine,
[0226][2-(2',6'-Dimethyl-biphenyl-3-yl)-ethyl]-methyl-amine,
[0227][2-(2',6'-Dimethyl-biphenyl-3-yl)-ethyl]-diethyl-amine,
[0228][2-(2',6'-Dimethyl-biphenyl-3-yl)-ethyl]-dipropyl-amine,
[0229][2-(2',6'-Dimethoxy-biphenyl-3-yl)ethyl]-dimethyl-amine,
[0230][2-(2',6'-Dimethoxy-biphenyl-3-yl)-ethyl]-methyl-amine,
[0231][2-(2',6'-Dimethoxy-biphenyl-3-yl)-ethyl]-diethyl-amine,
[0232][2-(2',6'-Dimethoxy-biphenyl-3-yl)-ethyl]-dipropyl-amine,
[0233][2-(2'-Methoxy-biphenyl-3-yl)-ethyl]-dimethyl-amine,
[0234][2-(2'-Methoxy-biphenyl-3-yl)-ethyl]-methyl-amine,
[0235]Diethyl-[2-(2'-methoxy-biphenyl-3-yl)-ethyl]-amine,
[0236][2-(2'-Methoxy-biphenyl-3-yl)-ethyl]dipropyl-amine,
[0237]2-(2',6'-Dimethoxy-biphenyl-3-yl)-ethylamine,
[0238][2-(6'-Chloro-2'-methoxy-biphenyl-3-yl)-ethyl]-dimethyl-amine,
[0239][2-(6'-Chloro-2'-methoxy-biphenyl-3-yl)-ethyl]-methyl-amine,
[0240][2-(2'-Methoxy-2-methyl-biphenyl-3-yl)-ethyl]-dimethyl-amine,
[0241][2-(2'-Methoxy-6-methyl-biphenyl-3-yl)-ethyl]-dimethyl-amine, or
[0242][2-(2',6'-Bis-trifluoromethyl-biphenyl-3-yl)-ethyl]-dimethyl-amine;
or [0243]2-(2',6'-Dichloro-biphenyl-3-yl)-ethyl]-dimethyl-amine, or
[0244][2-(2',6'-Difluoro-biphenyl-3-yl)-ethyl]-dimethyl-amine; or
[0245]{2-[3-(2-Methoxy-pyridin-3-yl)-phenyl]-ethyl}-dimethyl-amine, or
[0246]{2-[3-(2-Methoxy-pyridin-3-yl)-phenyl]-ethyl}-methyl-amine;

[0247]optionally in form of a salt, preferably a physiologically
acceptable salt, more preferably in form of a physiologically acceptable
acid addition salt, most preferably a hydrochloride salt, or a
corresponding solvate, or N-Oxide.

Also particularly preferred is a compound according to the invention,
which is a compound of GROUP B according to Formula Ia selected from
[0248][2-(2',6'-Dimethyl-biphenyl-3-yl)-ethyl]-dimethyl-amine,
[0249][2-(2',6'-Dimethyl-biphenyl-3-yl)-ethyl]-methyl-amine,
[0250][2-(2',6'-Dimethyl-biphenyl-3-yl)-ethyl]-diethyl-amine,
[0251][2-(2',6'-Dimethyl-biphenyl-3-yl)-ethyl]-dipropyl-amine,
[0252][2-(2',6'-Dimethoxy-biphenyl-3-yl)-ethyl]-dimethyl-amine,
[0253][2-(2',6'-Dimethoxy-biphenyl-3-yl)-ethyl]-methyl-amine,
[0254][2-(2',6'-Dimethoxy-biphenyl-3-yl)-ethyl]-diethyl-amine,
[0255][2-(2',6'-Dimethoxy-biphenyl-3-yl)-ethyl]-dipropyl-amine,
[0256][2-(2'-Methoxy-biphenyl-3-yl)-ethyl]-dimethyl-amine,
[0257][2-(2'-Methoxy-biphenyl-3-yl)-ethyl]-methyl-amine,
[0258]Diethyl-[2-(2'-methoxy-biphenyl-3-yl)-ethyl]-amine, or
[0259][2-(2'-Methoxy-biphenyl-3-yl)-ethyl]-dipropyl-amine,

[0260]optionally in form of a salt, preferably a physiologically
acceptable salt, more preferably in form of a physiologically acceptable
acid addition salt, most preferably a hydrochloride salt, or a
corresponding solvate.

[0261]In a further aspect the present invention also provides a process
for the preparation of compounds of general formula (I), according to
Scheme 1, wherein R1, R2, R3, R4, K, L, M, N and Z
have the meaning given above.

##STR00020##

[0262]The compounds of general formula (I) can be prepared by catalytic
cross-coupling reactions, which include the Kumada-Corriu-Tamao, Negishi,
Stille, Hiyama, Suzuki-Miyaura, Heck, Sonogashira and other
cross-coupling reactions known to those skilled in the art.

[0263]More preferably, the compounds of general formula (I) can be
prepared by cross-coupling Suzuki reaction of a compound of general
formula (VI)

##STR00021##

wherein R1, R2, R3, R4 and Z are as defined in claim
1, and X represents halogen, preferably Br, or an O-triflate group, is
reacted with a compound of general formula VII or VIIa

##STR00022##

wherein K, L, M, and N are as defined in claim 1, to form a compound
according to formula I, preferably in presence of a catalyst.

[0264]In a preferred embodiment of this process [0265]a) the catalyst is
a palladium catalyst with or without a ligand, and/or [0266]b) the
reaction is carried out in presence of at least one base, selected from
organic or inorganic bases and/or [0267]c) the reaction is carried out in
a suitable reaction medium selected from ethers, alcohols, hydrocarbons
or other organic solvents.

[0268]In a closely related aspect of the present invention is also
provided a process for the preparation of compounds of general formula
(I), wherein R1, R2, R3, R4, K, L, M, N and Z have
the meaning given above, according to which at least one compound of
general formula (VII) or (VIIa), (Scheme 1)

##STR00023##

wherein K, L, M and N have the meaning given above, is subjected to
cross-coupling Suzuki reaction with at least one compound of general
formula (VI),

##STR00024##

wherein R1, R2, R3, R4, and Z have the meaning given
above and X represent halogen, preferably bromide; or O-triflate group,
in a suitable reaction medium, in the presence of a palladium catalyst, a
suitable ligand and at least one base. This process can be performed by
subjecting the reaction mixture to 100° C. by conventional heating
for 20 h, or by microwave radiation for a period of time sufficient to
achieve the title compound (I), preferably for 1 to 10 minutes, and at a
temperature between 100 to 120° C.

[0269]The compounds of general formulas (VII) and (Vila) are either
commercially available or can be produced according to methods known to
those skilled in the art.

[0271]According to the invention, the bases that may be used in the
process are generally organic or inorganic bases, preferably alkali metal
hydroxides, e.g. sodium hydroxide or potassium hydroxide, or obtained
from other metals such as barium hydroxide or different carbonates,
preferably potassium carbonate, sodium carbonate, calcium carbonate or
alkoxydes, e.g. sodium methoxide potassium methoxide, sodium ethoxide,
potassium ethoxide or potassium tert-butoxide, or organic amines,
preferably triethylamine, diisopropylethylamine or heterocycles, e.g.
1,4-diazabicyclo[2.2.2]octane, 1,8-diazabicyclo5.4.0]undec-7-ene,
pyridine, diamino pydine, dimethylaminopyridine, methylpiperidine or
morpholine. Alkali metals such as sodium or its hydrides, e.g. sodium
hydride, may also be used.

[0272]Preparation of compounds of general formula (VI) can be achieved by
reductive amination reaction of aldehydes of general formula (VIII),

##STR00025##

wherein R2 have the meaning given above, with a compound of general
formula (IX),

##STR00026##

wherein R1, R3, R4, X and Z have the meaning given above.
The reductive amination is performed by subjecting a reaction mixture
comprising a compound of general formula (VIII), and amino compound of
general formula (IX) and a reducing agent in a suitable reaction medium,
for a period of time sufficient to achieve the title compound (VI). The
reductive amination reaction can also be performed under microwave
radiation for a period of time sufficient to achieve the title compound
(VI), preferably for 1 to 10 minutes, and at a temperature between 90 to
120° C. The use of microwave irradiation limits the formation of
undesirable secondary reaction products, compared to what is obtained in
a conventional reductive amination procedure.

[0273]This process can be performed as a direct reaction when the carbonyl
compound of general formula (VIII) and the amine compound of general
formula (IX) are mixed with the reducing agent without prior formation of
the intermediate imine or iminium salt. A stepwise or indirect reaction
involves the reduction of the preformatted imine in a separate step.

[0276]Preparation of compounds of general formula (IX) can be achieved by
reductive amination reaction of aldehydes of general formula (X),

##STR00027##

wherein R1 have the meaning given above, with a compound of general
formula (XI),

##STR00028##

wherein R3, R4, X and Z have the meaning given above. The
reductive amination is performed in the same conditions described above.

[0277]In the case that R1 and R2 have the same meaning, the
preparation of compound with general formula (VI) can be achieved by
direct reductive amination reaction of at least 2 equivalents of the
corresponding aldehyde and compound with general formula (XI).

[0278]The compounds of general formulas (VIII) and (X) are either
commercially available or can be produced according to methods known to
those skilled in the art.

[0279]The preparation of compounds of general formula (I) is illustrated
in scheme 1:

##STR00029##

[0280]In another aspect, the present invention also provides a process for
the preparation of compounds of general formula (Ia), according to Scheme
2, wherein R1, R2, R3, R4, and A have the meaning
given above.

##STR00030##

[0281]The compounds of general formula (Ia) can be prepared by
cross-coupling Suzuki reaction of boronic acids or boronate esters of
general formula (XII) or (XIla),

##STR00031##

wherein A have the meaning given above, with at least one compound of
general formula (XIII),

##STR00032##

wherein R1, R2, R3 and R4, have the meaning given
above and X represent halogen, preferably bromide or O-triflate group, in
a suitable reaction medium, in the presence of a palladium catalyst, a
suitable ligand and at least one base. This process can be performed by
subjecting the reaction mixture to 100° C. by conventional heating
for 20 h, or by microwave radiation for a period of time sufficient to
achieve the title compound (I), preferably for 1 to 10 minutes, and at a
temperature between 100 to 120° C.

[0282]The compounds of general formulas (XII) and (XIla) are either
commercially available or can be produced according to methods known to
those skilled in the art.

[0283]Suitable reaction media are those described above.

[0284]The bases that may be used in the process are those described above.

[0285]Preparation of compounds of general formula (XIII) can be achieved
by reductive amination reaction of aldehydes of general formula (VIII),

##STR00033##

wherein R2 have the meaning given above, with a compound of general
formula (XIV),

##STR00034##

wherein R1, R3, X and R4 have the meaning given above. The
reductive amination is performed by subjecting a reaction mixture
comprising a compound of general formula (VIII), and amino compound of
general formula (XIV) and a reducing agent, in a suitable reaction
medium, for a period of time sufficient to achieve the title compound
(XIII). The reductive amination reaction can also be performed under
microwave radiation for a period of time sufficient to achieve the title
compound (XIII), preferably for 1 to 10 minutes, and at a temperature
between 90 to 120° C. The use of microwave irradiation limits the
formation of undesirable secondary reaction products, compared to what is
obtained in a conventional reductive amination procedure.

[0286]This process can be performed as a direct reaction when the carbonyl
compound of general formula (VIII) and the amine compound of general
formula (XIV) are mixed with the reducing agent without prior formation
of the intermediate imine or iminium salt. A stepwise or indirect
reaction involves the reduction of the preformatted imine in a separate
step.

[0287]The choice of the reducing agent can be conventionally made by those
skilled in the art. Reducing agents useful in this procedure are those
described above.

[0288]Suitable reaction media are those described above.

[0289]Preparation of compounds of general formula (XIV) can be achieved by
reductive amination reaction of aldehydes of general formula (X),

##STR00035##

wherein R1 have the meaning given above, with a compound of general
formula (XV),

##STR00036##

wherein R3 and R4 and X have the meaning given above. The
reductive amination is performed in the same conditions described above.

[0290]In the case that R1 and R2 have the same meaning, the
preparation of compound with general formula (XIII) can be achieved by
direct reductive amination reaction of at least 2 equivalents of the
corresponding aldehyde and compound with general formula (XV).

[0291]The preparation of compounds of general formula (Ia) is illustrated
in scheme 2:

##STR00037##

[0292]In another aspect, the present invention also provides an
alternative process for the preparation of compounds of general formula
(Ia), according to Scheme 3, wherein R1, R2, R3, and
R4, have the meaning given above and A is:

##STR00038##

wherein R6, R7 and R8 have the meaning described above.
This a very suitable process, also when R3 and R4 are both
hydrogen.

[0293]The compounds of general formula (XVI),

##STR00039##

wherein R1, R2, R3, R4, R6 and R7 have the
meaning described above were reacted with compounds of general formula
(XVII),

##STR00040##

wherein R8 have the meaning described above, in a suitable reaction
media to give the title compounds of general formula Ia.

[0294]Preparation of compounds of general formula (XVI) can be achieved by
Cu catalyzed nucleophilic substitution reaction of compounds of general
formula (XVIII),

##STR00041##

wherein R6 and R7 have the meaning described above, with
compounds of general formula (XIII),

##STR00042##

wherein R1, R2, R3 and R4, have the meaning given
above and X represent halogen, preferably iodide or bromide in a suitable
reaction medium, in the presence of CuX, and at least one base.

[0295]The compounds of general formulas (XVII) and (XVIII) are either
commercially available or can be produced according to methods known to
those skilled in the art.

[0296]Suitable reaction media are those described above.

[0297]The bases that may be used in the process are those described above.

[0298]This alternative preparation of compounds of general formula (Ia) is
illustrated in scheme 3:

##STR00043##

[0299]In a further aspect, the present invention also provides an
alternative process for the preparation of compounds of general formula
(Ia), according to Scheme 4. According to this process, at least one
compound of general formula (XVIII),

##STR00044##

wherein R1, R2, R3 and R4 have the meaning given above
and X represents halogen, preferably bromide, is subjected to
Kumada-Corriu cross-coupling reaction with at least one compound of
general formula (XIX),

A-X (XIX)

wherein A has the meaning given above and X represents halogen, preferably
bromide, in a suitable reaction medium, in the presence of a palladium
catalyst, a suitable ligand and at least one base. This process can be
performed by subjecting the reaction mixture to 50° C. to
conventional heating for 48 h, or by microwave radiation for a period of
time sufficient to achieve the title compound (Ia), preferably for 30 to
60 minutes, and at a temperature between 100 to 120° C.

[0300]Preparation of compounds of general formula (XVIII) can be achieved
by Grignard reaction of compounds of general formula (XIII),

##STR00045##

wherein R1, R2, R3 and R4 have the meaning given above
and X represents halogen, preferably bromide. The Grignard reaction with
magnesium and in a suitable solvent, preferably tetrahydrofuran can be
performed by subjecting the reaction mixture to 50° C. by
conventional heating for a period of time sufficient to achieve the title
compound (XVIII), or by microwave radiation 20 to 30 minutes, and at a
temperature between 100 to 120° C.

[0301]The compounds of general formula (XIX) are either commercially
available or can be produced according to methods known to those skilled
in the art.

[0302]The synthesis of compounds of general formula (XIII) can be
performed through any of the methods described above (schemes 1, 2 and
3).

[0303]Suitable reaction media are those described above.

[0304]The bases that may be used in the process are those described above.

[0305]This alternative method for the preparation of compounds of general
formula (Ia) is illustrated in scheme 4:

##STR00046##

[0306]In a further aspect, the present invention also provides an
alternative process for the preparation of compounds of general formula
(Ia), according to Scheme 5. According to this process, at least one
compound of general formula (XX),

##STR00047##

wherein R1, R2, R3 and R4 have the meaning given
above, is subjected to Stille cross-coupling reaction with at least one
compound of general formula (XIX),

A-X (XIX)

wherein A has the meaning given above and X represents halogen, preferably
bromide, in a suitable reaction medium, in the presence of a palladium
catalyst, a suitable ligand and at least one base. This process can be
performed by subjecting the reaction mixture to conventional heating, or
by microwave radiation for a period of time sufficient to achieve the
title compound (Ia).

[0307]Preparation of compounds of general formula (XX) can be achieved by
reaction of 1,1,1,2,2,2-hexamethyl-distannane with compounds of general
formula (XIII),

[0308]The compounds of general formula (XIX) are either commercially
available or can be produced according to methods known to those skilled
in the art.

[0309]The synthesis of compounds of general formula (XIII) can be
performed through any of the methods described above (schemes 1, 2 and
3).

[0310]Suitable reaction media are those described above.

[0311]The bases that may be used in the process are those described above.

[0312]This alternative method for the preparation of compounds of general
formula (Ia) is illustrated in scheme 5:

##STR00049##

[0313]In another aspect, the present invention also provides an
alternative process for the preparation of compounds of general formula
(Ia), according to Scheme 6, wherein R1, R2, R3, and
R4, have the meaning given above and A is:

##STR00050##

wherein R6, R7 and R8 have the meaning described above.
This is a very suitable process, also when R3 and R4 are both
hydrogen.

[0314]The compounds of general formula (XXI),

##STR00051##

wherein R1, R3, R4 and A have the meaning described above,
undergo reductive amination reaction in the conditions described above
(schemes 1, 2 and 3) and with compounds of general formula (VIII),

##STR00052##

wherein R2 has the meaning given above.

[0315]Preparation of compounds of general formula (XXI) can be achieved by
reductive amination of aldehydes of general formula (X),

##STR00053##

wherein R1 has the meaning given above, with a compound of general
formula (XXII),

##STR00054##

wherein R3, R4 and X have the meaning given above. The reductive
amination is performed in the same conditions described above.

[0316]In the case that R1 and R2 have the same meaning, the
preparation of compounds with general formula (Ia) can be achieved by
direct reductive amination reaction of at least 2 equivalents of the
corresponding aldehyde and a compound of general formula (XXII).

[0317]The compounds of general formula (XXII) can be obtained by
simultaneous reduction of nitro and double bond moieties of compounds of
general formula (XXIII),

##STR00055##

wherein R3, R4 and A have the meaning given above.

[0318]Nitroaldol reaction using nitromethane in a suitable reaction medium
of aldehydes of general formula (XXIV),

##STR00056##

wherein R3, R4 and A have the meaning given above, affords
compounds of general formula (XWI).

[0319]The synthesis of compounds of general formula (XXIV) is performed by
treatment of compounds of general formula (XXV) with magnesium, followed
by formylation with dimethylformamide,

##STR00057##

wherein R3, R4 and A have the meaning given above and X
represents halogen, preferably bromide.

[0320]Formylation that leads to compounds with general formula (XXIV) can
also be performed from different starting materials as non-halogenated,
acid, or acid derivative compounds, and through other methods known to
those skilled in the art.

[0321]Compounds of general formula (XXV) are obtained from compounds of
general formula (XXVI),

##STR00058##

wherein R3, R4, R6 and R7 have the meaning given above
and X represents halogen, preferably bromide, through ring closing
reaction with hydrazines of general formula (XVII),

##STR00059##

wherein R8 have the meaning given above.

[0322]Acetylation reaction in a suitable reaction medium and with a base
of compounds of general formula (XXVII),

##STR00060##

wherein R3, R4 and R6 have the meaning given above and X
represents halogen, preferably bromide, with nitrophenyl esters of
general formula (XXVIII),

##STR00061##

wherein R8 has the meaning given above, yields the compounds of
general formula (XXVI).

[0323]The compounds of general formulas (XXVII), (XXVIII), (XVII), (X) and
(VIII) are either commercially available or can be produced according to
methods known to those skilled in the art.

[0324]Suitable reaction media are those described above.

[0325]The bases and reducing agents that may be used in the process are
those described above.

[0326]This alternative method for the preparation of compounds of general
formula (Ia) is illustrated in scheme 6:

##STR00062## ##STR00063##

[0327]In a further aspect, the present invention also provides an
alternative process for the preparation of intermediate compounds of
general formula (XXII), which can be converted into the target compounds
of general formula (Ia) following the methods described above (Scheme 6).
Compounds of general formula (XXII) can be prepared according to Scheme
7. According to this process, at least one compound of general formula
(XXIX),

##STR00064##

wherein A, R3 and R4 have the meaning described above, is
subjected to catalytic hydrogenation to afford the amine compounds of
general formula (XXII).

[0328]Compounds of general formula (XXIX) can be prepared by treatment of
the corresponding mesylate of general formula (XXX) with a cyanide salt,

##STR00065##

wherein A, R3 and R4 have the meaning described above. Mesylate
compounds of general formula (XXX) can be produced from hydroxyl
compounds of general formula (XXXI) through treatment with
methanesulfonyl chloride,

##STR00066##

wherein A, R3 and R4 have the meaning described above. Compounds
of general formula (XXXI) are prepared by reduction with a suitable
reducing agent of benzoic acids with general formula (XXXII),

##STR00067##

wherein A, R3 and R4 have the meaning described above.

[0329]In the particular case that A is:

##STR00068##

wherein R6, R7 and R8 have the meaning described above, the
benzoic acid compounds of general formula (XXXII) can be prepared from
compounds of general formula (XXXIII),

##STR00069##

wherein R3, R4, R6 and R7 have the meaning described
above, by ring closing reaction with hydrazine compounds of general
formula (XVII).

##STR00070##

wherein R8 have the meaning described above.

[0330]Acetylation reaction in a suitable reaction medium and with a base
of compounds of general formula (XXXIV),

##STR00071##

wherein R3, R4 and R6 have the meaning given above, with
nitrophenyl esters of general formula (XXVIII),

##STR00072##

wherein R8 has the meaning given above, yields the compounds of
general formula (XXXIII).

[0331]The compounds of general formulas (X00(1V) and (XVII) are either
commercially available or can be produced according to methods known to
those skilled in the art.

[0332]Suitable reaction media are those described above.

[0333]The bases and reducing agents that may be used in the process are
those described above.

[0334]This alternative method for the preparation of intermediate
compounds of general formula(XXII) is illustrated in scheme 7:

##STR00073##

[0335]In another aspect, the present invention also provides an
alternative process for the preparation of intermediate compounds of
general formula (XXII), according to Scheme 8. According to this process,
deprotection with catalytic hydrogenation of at least one compound of
general formula (XXXV),

##STR00074##

wherein R3, R4 and A have the meaning given above, affords amine
compounds of general formula (XXII).

[0336]Compounds of general formula (XXXV) can be obtained by Suzuki
cross-coupling reaction of hydroborated benzyl vinylcarbamate with at
least one compound of general formula (XXV),

##STR00075##

wherein R3, R4 and A have the meaning given above and X
represents halogen, preferably bromide. The cross-coupling reaction is
performed in a suitable reaction medium, in the presence of a palladium
catalyst, a suitable ligand and at least one base.

[0337]Compounds of general formula (XXV) are obtained as described above
(scheme 6).

[0338]Hydroborated benzyl vinylcarbamate can be prepared as previously
described by Kamatani and Overman (J. Org. Chem., 1999, 64, 8743).

[0339]Suitable reaction media are those described above.

[0340]The bases that may be used in the process are those described above.

[0341]This alternative method for the preparation of intermediate
compounds of general formula (XXII) is illustrated in scheme 8:

##STR00076##

[0342]In another aspect, the present invention provides an alternative
process for the preparation of intermediate compounds of general formula
(XXII), according to Scheme 9. According to this process, deprotection
with hydrazine of at least one compound of general formula (XXXVI),

##STR00077##

wherein R3, R4 and A have the meaning given above, affords amine
compounds of general formula (XXII).

[0343]Compounds of general formula (XXXVI) are prepared by catalytic
hydrogenation of unsaturated compounds of general formula (XXXVII),

##STR00078##

wherein R3, R4 and A have the meaning given above. Compounds of
general formula (XXXVII) can be obtained by Heck cross-coupling reaction
of vinyl phtalimide with compounds of general formula (XXV),

##STR00079##

wherein R3, R4 and A have the meaning given above and X
represents halogen, preferably bromide. The Heck reaction is performed in
a suitable reaction medium, in the presence of a palladium catalyst, a
suitable ligand and at least one base.

[0344]Compounds of general formula (XXV) are obtained as described above
(scheme 6).

[0345]Suitable reaction media are those described above.

[0346]The bases that may be used in the process are those described above.

[0347]This alternative method for the preparation of intermediate
compounds of general formula (XXII) is illustrated in scheme 9:

##STR00080##

[0348]In a further aspect, the present invention also provides an
alternative process for the preparation of intermediate compounds of
general formula (XXXVIII), according to scheme 10,

##STR00081##

wherein R3, R4 and A have the meaning described above and Y is
any halogen (intermediate compounds with general formula (XXV)), acid
(intermediate compounds with general formula (XXXII)), acid derivative or
any other reactive group which allows chemical transformations through
any of the methods described above (Schemes 1 to 9) to obtain the target
compounds of general formula (Ia).

[0349]The intermediate compounds of general formula (XXXVIII) can be
prepared by cross-coupling Suzuki reaction of boronic acids or boronate
esters of general formula (XXXIX) or (XXXIXa),

##STR00082##

wherein R3, R4 and Y, have the meaning described above, with at
least one compound of general formula (XIX),

A-X (XIX)

wherein A has the meaning given above and X represents halogen, preferably
bromide, in a suitable reaction medium, in the presence of a palladium
catalyst, a suitable ligand and at least one base. This process can be
performed by subjecting the reaction mixture to conventional heating, or
by microwave radiation for a period of time sufficient to achieve the
compounds of general formula (XXXVIII).

[0350]The compounds of general formulas (XXXIX), (XXXIXa) and (XIX) are
either commercially available or can be produced according to methods
known to those skilled in the art.

[0351]Suitable reaction media are those described above.

[0352]The bases that may be used in the process are those described above.

[0353]This alternative method for the preparation of intermediate compound
(XXXVIII) is illustrated in scheme 10:

##STR00083##

[0354]In a further aspect, the present invention also provides an
alternative process for the preparation of compounds of general formula
(XXI), according to scheme 11, in the particular case of R1=-Me
(compounds of general formula (XL)). According to this process, compounds
of general formula (XL),

##STR00084##

wherein R3, R4 and A have the meaning described above, can be
obtained by treatment of compounds of general formula (XLI) with a
reducing agent in a suitable reaction media,

##STR00085##

wherein R3, R4 and A have the meaning described above.

[0355]Boc protection of compounds of general formula (XXII),

##STR00086##

wherein R3, R4 and A have the meaning described above, can be
effected by treatment with di-tert-butyl dicarbonate, in a suitable
reaction medium and in the presence of a base.

[0356]Compounds of general formula (XXII) are obtained as described above
(scheme 6, 7, 8 and 9).

[0357]Suitable reaction media are those described above.

[0358]The bases and reducing agents that may be used in the process are
those described above.

[0359]This method for the preparation of compounds of general formula (XL)
is illustrated in scheme 11:

##STR00087##

[0360]In another aspect, the present invention also provides an
alternative process for the preparation of compounds of general formula
(XXI), according to scheme 12, wherein R1, R3, R4 and A
have the meaning given above.

##STR00088##

[0361]The compounds of general formula (XXI) can be prepared by
deprotection in refluxing methanol of carbamate compounds of general
formula (XLII),

##STR00089##

wherein R1, R3, R4 and A have the meaning given above.

[0362]Compounds of general formula (XLII) can be obtained by treatment
with 1-chloroethyl chloroformate in a suitable reaction medium and in the
presence of a base of compounds of general formula (Ia),

##STR00090##

wherein R1, R3, R4 and A have the meaning described above.
This is a very suitable process in the particular case where R2 is
methyl group.

[0363]Compounds of general formula (Ia) are obtained as described above
(scheme 2, 3, 4, 5 and 6).

[0364]Suitable reaction media are those described above.

[0365]The bases that may be used in the process are those described above.

[0366]This alternative method for the preparation of compounds of general
formula (XXI) is illustrated in scheme 12:

##STR00091##

[0367]In a further aspect the present invention also provides a process
for the preparation of salts of compounds of general formula (I), wherein
at least one compound of general formula (I) is reacted with an inorganic
and/or organic acid, preferably in the presence of a suitable reaction
medium. Suitable reaction media are the ones given above. Suitable
inorganic acid are for example hydrochloric acid, hydrobromic acid,
phosphoric acid, sulphuric acid, nitric acid. Suitable organic acids are
e.g. citric acid, maleic acid, furmaric acid, tartaric acid or
derivatives thereof, such as p-toluenesulfonic acid, methanesulfonic acid
or camphersulfonic acid.

[0368]In yet a further aspect the present invention also provides a
process for the preparation of salts of compounds of general formula (I),
wherein at least one compound of general formula (I) having at least one
acidic group is reacted with one or more suitable bases, preferably in
the presence of suitable reaction medium. Suitable bases are e.g.
hydroxides. Carbonates or alkoxides, which include suitable cations,
derived e.g. from alkaline metals, alkaline earth metals or organic
cations, e.g. [NHnR4-n].sup.+, wherein n is 0, 1, 2, 3 or 4 and
R represents a branched or linear C1-4 alkyl radical.

[0369]Solvates, preferably hydrates, of the phenylamino-substituted
piperidine compounds of general formula (I), or corresponding
stereoisomers, or corresponding salts may also be obtained by standard
procedures known to those skilled in the art.

[0370]If the compounds of general formula (I) are obtained in form of a
mixture of stereoisomers, particularly enantiomers or diastereomers, said
mixtures may be separated by standard procedures known to those skilled
in the art, e.g. chromatographic methods of crystallization with chiral
reagents.

[0371]The purification and isolation of the phenylamino-substituted
piperidine compounds of general formula (I) or a corresponding
stereoisomer, or a corresponding salt, or corresponding solvate
respectively, if required may be carried out by conventional methods
known to those skilled in the art, e.g. chromatographic methods or
recrystallization.

[0372]The compounds of general formula (I), their stereoisomers or the
respective salts or solvates are toxicologically acceptable and are
therefore suitable as pharmaceutical active substances for the
preparation of medicaments.

[0373]The present invention therefore also provides for a pharmaceutical
formulation or medicament comprising at least one compound according to
formula I,

##STR00092##

wherein

[0374]K-L-M-N together form [0375]═CH--X--Y═CH--; in which any
suitable H may be substituted by R6 and/or R7, and in which X
is selected from NR8, O or S, while Y is selected from N or CH;
[0376]═CH--X--Y--C(O)--; in which any suitable H may be substituted
by R6 and in which one of X and Y is NR8, while the other is
selected from NR8a, S or O; [0377]═CH--X--Y--C(O)--; in which
one of X and Y is CH2, while the other is selected from NR8, S
or O, in which any suitable H may be substituted by R6 and/or
R7; [0378]═CR6--N═N--C(O)--;
[0379]═CR9--CH═CH--CH═CH--; in which any suitable H may
be substituted by R6;
[0380]═CR9--CH═CH--CH═CR9a--; in which any suitable
H may be substituted by R6; [0381]═CH--X═Y--CH═CH--; in
which any suitable H may be substituted by R6 and/or R7, and in
which one of X or Y is selected from N, while the other is selected from
N or CH; [0382]═CH--X═Y--CH2--CH2--; in which any
suitable H may be substituted by R6 and/or R7, and in which one
of X or Y is selected from N, while the other is selected from N or CH;
[0383]═CH--X--Y--CH═CH--; in which any suitable H may be
substituted by R6 and/or R7, and in which one of X or Y is
selected from NR8, O or S while the other is selected from NR8a
or CH2; [0384]═CH--X--Y--CH2--CH2--; in which any
suitable H may be substituted by R6 and/or R7, and in which one
of X or Y is selected from NR8, O or S while the other is selected
from NR8a or CH2; [0385]═CH--X--CH2--Y═CH--; in
which any suitable H may be substituted by R6 and/or R7, and in
which X is selected from NR8, O or S while Y is selected from N or
CH; [0386]═CH--X--CH═Y--CH2--; in which any suitable H may
be substituted by R6 and/or R7, and in which X is selected from
NR8, O or S while Y is selected from N or CH;
[0387]═CH--N═CH--Y═CH--; in which any suitable H may be
substituted by R6 and/or R7;
[0388]═CH--X--CH2--Y--CH2--; in which any suitable H may be
substituted by R6 and/or R7, and in which one of X or Y is
selected from NR8, O or S while the other is selected from
NR8a, O, S or CH2;

[0389]R1 and R2 each are independently selected from the group
consisting of hydrogen; or a linear or branched, saturated or
unsaturated, optionally at least mono-substituted aliphatic radical; or

[0390]R1 and R2 together with the bridging nitrogen atom form an
saturated or unsaturated, optionally at least mono-substituted 5- or
6-membered-heterocyclic ring, which may be condensed with an optionally
at least mono-substituted mono- or polycyclic ring system;

[0391]Z is selected from [0392]--(CH2)n--, with n being 1, 2,
3 or 4; [0393]--O--(CH2)n--, with n being 1, 2, 3 or 4;
[0394]--S--(CH2)n--, with n being 1, 2, 3 or 4;
[0395](CH2)n--(CHR5)--(CH2)m, with n and m being
selected from 0, 1, 2 or 3 and m+n being 1, 2 or 3, with R5 being
selected from F, Cl, Br, I, OH, SH, or unsubstituted C1-4-Alkyl;

[0396]R3 and R4 are independently from each other selected from
hydrogen; halogen, OH, SH, NH2; a linear or branched, saturated or
unsaturated, optionally at least mono-substituted aliphatic radical; or
O--R with R being a linear or branched, saturated or unsaturated,
optionally at least mono-substituted aliphatic radical;

[0397]R6 and R7 are independently from each other selected from
hydrogen; halogen, OH, SH, NH2; an aliphatic radical, which is
linear or branched, saturated or unsaturated, and optionally at least
mono-substituted by F, Cl, Br, I, SH or OH; or O--R with R being an
aliphatic radical, which is linear or branched, saturated or unsaturated,
and optionally at least mono-substituted by F, Cl, Br, I, SH or OH;

[0398]R8 and R9a are independently from each other selected from
hydrogen; or an aliphatic radical, which is linear or branched, saturated
or unsaturated, and optionally at least mono-substituted by F, Cl, Br, I,
SH or OH;

[0399]R9 and R9a are independently from each other selected from
an aliphatic radical, which is linear or branched, saturated or
unsaturated, and optionally at least mono-substituted by F, Cl, Br, I, SH
or OH; or O--R with R being an aliphatic radical, which is linear or
branched, saturated or unsaturated, and optionally at least
mono-substituted by F, Cl, Br, I, SH or OH; or R9 and R9a both
are identical and selected from F, or Cl;

[0400]preferably R9 and R9a are independently from each other
selected from an aliphatic radical, which is linear or branched,
saturated or unsaturated, and optionally at least mono-substituted by F,
Cl, Br, I, SH or OH; or O--R with R being an aliphatic radical, which is
linear or branched, saturated or unsaturated, and optionally at least
mono-substituted by F, Cl, Br, I, SH or OH; optionally in form of one of
its stereoisomers, preferably enantiomers or diastereomers, its racemate
or in form of a mixture of at least two of its stereoisomers in any
mixing ratio; or in form of a salt, preferably a physiologically
acceptable salt thereof, or a solvate, or N-oxide, respectively, and
optionally one or more pharmaceutically acceptable adjuvants.

[0401]In a preferred embodiment of the above medicament according to the
invention the medicament comprises at least one compound according to
formula Ia,

##STR00093##

wherein

[0402]A is a compound selected from the following group

##STR00094##

preferably

##STR00095##

[0403]R1 and R2 each are independently selected from the group
consisting of hydrogen; or a linear or branched, saturated or
unsaturated, optionally at least mono-substituted aliphatic radical; or

[0404]R1 and R2 together with the bridging nitrogen atom form an
saturated or unsaturated, optionally at least mono-substituted 5- or
6-membered-heterocyclic ring, which may be condensed with an optionally
at least mono-substituted mono- or polycyclic ringsystem,

[0405]R3 and R4 are independently from each other selected from
hydrogen; halogen, OH, SH, NH2; a linear or branched, saturated or
unsaturated, optionally at least mono-substituted aliphatic radical; or
O--R with R being a linear or branched, saturated or unsaturated,
optionally at least mono-substituted aliphatic radical;

[0406]R6 and R7 are independently from each other selected from
hydrogen; halogen, OH, SH, NH2; an aliphatic radical, which is
linear or branched, saturated or unsaturated, and optionally at least
mono-substituted by F, Cl, Br, I, SH or OH; or O--R with R being an
aliphatic radical, which is linear or branched, saturated or unsaturated,
and optionally at least mono-substituted by F, Cl, Br, I, SH or OH;

[0407]R8 and R8a are independently from each other selected from
hydrogen; or an aliphatic radical, which is linear or branched, saturated
or unsaturated, and optionally at least mono-substituted by F, Cl, Br, I,
SH or OH;

[0408]R9 and R9a are independently from each other selected from
an aliphatic radical, which is linear or branched, saturated or
unsaturated, and optionally at least mono-substituted by F, Cl, Br, I, SH
or OH; or O--R with R being an aliphatic radical, which is linear or
branched, saturated or unsaturated, and optionally at least
mono-substituted by F, Cl, Br, I, SH or OH; or R9 and R9a both
are identical and selected from F, or Cl;

[0409]preferably R9 and R9a are independently from each other
selected from an aliphatic radical, which is linear or branched,
saturated or unsaturated, and optionally at least mono-substituted by F,
Cl, Br, I, SH or OH; or O--R with R being an aliphatic radical, which is
linear or branched, saturated or unsaturated, and optionally at least
mono-substituted by F, Cl, Br, I, SH or OH;

[0410]optionally in form of one of its stereoisomers, preferably
enantiomers or diastereomers, its racemate or in form of a mixture of at
least two of its stereoisomers in any mixing ratio; or in form of a salt,
preferably a physiologically acceptable salt thereof, or a solvate, or
N-oxide, respectively, and optionally one or more pharmaceutically
acceptable adjuvants.

[0411]In another preferred embodiment of the above medicament according to
the invention the medicament comprises at least one compound according to
formula Ia,

##STR00096##

wherein

[0412]A is a compound selected from the following group

##STR00097##

preferably

##STR00098##

[0413]R1 and R2 each are independently selected from the group
consisting of hydrogen; or a linear or branched, saturated or
unsaturated, optionally at least mono-substituted aliphatic radical; or

[0414]R1 and R2 together with the bridging nitrogen atom form an
saturated or unsaturated, optionally at least mono-substituted 5- or
6-membered-heterocyclic ring, which may be condensed with an optionally
at least mono-substituted mono- or polycyclic ringsystem,

[0415]R3 and R4 are independently from each other selected from
hydrogen; halogen, OH, SH, NH2; a linear or branched, saturated or
unsaturated, optionally at least mono-substituted aliphatic radical; or
O--R with R being a linear or branched, saturated or unsaturated,
optionally at least mono-substituted aliphatic radical;

[0416]R6 is selected from hydrogen; halogen, OH, SH, NH2; an
aliphatic radical, which is linear or branched, saturated or unsaturated,
and optionally at least mono-substituted by F, Cl, Br, I, SH or OH; or
O--R with R being an aliphatic radical, which is linear or branched,
saturated or unsaturated, and optionally at least mono-substituted by F,
Cl, Br, I, SH or OH;

[0417]R9 and R9a are independently from each other selected from
an aliphatic radical, which is linear or branched, saturated or
unsaturated, and optionally at least mono-substituted by F, Cl, Br, I, SH
or OH; or O--R with R being an aliphatic radical, which is linear or
branched, saturated or unsaturated, and optionally at least
mono-substituted by F, Cl, Br, I, SH or OH; or R9 and R9a both
are identical and selected from F, or Cl;

[0418]preferably R9 and R9a are independently from each other
selected from an aliphatic radical, which is linear or branched,
saturated or unsaturated, and optionally at least mono-substituted by F,
Cl, Br, I, SH or OH; or O--R with R being an aliphatic radical, which is
linear or branched, saturated or unsaturated, and optionally at least
mono-substituted by F, Cl, Br, I, SH or OH;

[0419]optionally in form of one of its stereoisomers, preferably
enantiomers or diastereomers, its racemate or in form of a mixture of at
least two of its stereoisomers in any mixing ratio; or in form of a salt,
preferably a physiologically acceptable salt thereof, or a solvate, or
N-oxide, respectively, and optionally one or more pharmaceutically
acceptable adjuvants.

[0420]Another aspect of the invention is a medicament/pharmaceutical
composition comprising at least one compound according to the invention,
optionally in form of one of its stereoisomers, preferably enantiomers or
diastereomers, its racemate or in form of a mixture of at least two of
its stereoisomers in any mixing ratio; or in form of a salt, preferably a
physiologically acceptable salt thereof, or a solvate, or N-oxide,
respectively, and optionally one or more pharmaceutically acceptable
adjuvants.

[0421]Furthermore, the present invention also provides for a
pharmaceutical composition/medicament comprising at least one compound of
general formula (I), optionally in form of one of its stereoisomers,
preferably enantiomers or diastereomers, its racemate or in form of a
mixture of at least two of its stereoisomers in any mixing ratio, or a
physiologically acceptable salt thereof, or a solvate, respectively, and
optionally one or more pharmaceutically acceptable adjuvants, which is
not yet formulated into a medicament.

[0423]The present invention also provides for the use of at least one
compound according to formula I,

##STR00099##

wherein

[0424]K-L-M-N together form [0425]═CH--X--Y═CH--; in which any
suitable H may be substituted by R6 and/or R7, and in which X
is selected from NR8, O or S, while Y is selected from N or CH;
[0426]═CH--X--Y--C(O)--; in which any suitable H may be substituted
by R6 and in which one of X and Y is NR8, while the other is
selected from NR8a, S or O; [0427]═CH--X--Y--C(O)--; in which
one of X and Y is CH2, while the other is selected from

[0428]NR8, S or O, in which any suitable H may be substituted by
R6 and/or R7; [0429]═CR6--N═N--C(O)--;
[0430]═CR9--CH═CH--CH═CH--; in which any suitable H may
be substituted by R6;
[0431]═CR9--CH═CH--CH═CR9a--; in which any suitable
H may be substituted by R6; [0432]═CH--X═Y--CH═CH--; in
which any suitable H may be substituted by R6 and/or R7, and in
which one of X or Y is selected from N, while the other is selected from
N or CH; [0433]═CH--X═Y--CH2--CH2--; in which any
suitable H may be substituted by R6 and/or R7, and in which one
of X or Y is selected from N, while the other is selected from N or CH;
[0434]═CH--X--Y--CH═CH--; in which any suitable H may be
substituted by R6 and/or R7, and in which one of X or Y is
selected from NR8, O or S while the other is selected from NR8a
or CH2; [0435]═CH--X--Y--CH2--CH2--; in which any
suitable H may be substituted by R6 and/or R7, and in which one
of X or Y is selected from NR8, O or S while the other is selected
from NR8a or CH2; [0436]═CH--X--CH2--Y═CH--; in
which any suitable H may be substituted by R6 and/or R7, and in
which X is selected from NR8, O or S while Y is selected from N or
CH; [0437]═CH--X--CH═Y--CH2--; in which any suitable H may
be substituted by R6 and/or R7, and in which X is selected from
NR8, O or S while Y is selected from N or CH;
[0438]═CH--N═CH--Y═CH--; in which any suitable H may be
substituted by R6 and/or R7;
[0439]═CH--X--CH2--Y--CH2--; in which any suitable H may be
substituted by R6 and/or R7, and in which one of X or Y is
selected from NR8, O or S while the other is selected from
NR8a, O, S or CH2;

[0440]R1 and R2 each are independently selected from the group
consisting of hydrogen; or a linear or branched, saturated or
unsaturated, optionally at least mono-substituted aliphatic radical; or

[0441]R1 and R2 together with the bridging nitrogen atom form an
saturated or unsaturated, optionally at least mono-substituted 5- or
6-membered-heterocyclic ring, which may be condensed with an optionally
at least mono-substituted mono- or polycyclic ringsystem;

[0442]Z is selected from [0443]--(CH2)n--, with n being 1, 2,
3 or 4; [0444]--O--(CH2)n--, with n being 1, 2, 3 or 4;
[0445]--S--(CH2)n--, with n being 1, 2, 3 or 4;
[0446](CH2)n--(CHR5)--(CH2)m, with n and m being
selected from 0, 1, 2 or 3 and m+n being 1, 2 or 3, with R5 being
selected from F, Cl, Br, I, OH, SH, or unsubstituted C1-4-Alkyl;

[0447]R3 and R4 are independently from each other selected from
hydrogen; halogen, OH, SH, NH2; a linear or branched, saturated or
unsaturated, optionally at least mono-substituted aliphatic radical; or
O--R with R being a linear or branched, saturated or unsaturated,
optionally at least mono-substituted aliphatic radical;

[0448]R6 and R7 are independently from each other selected from
hydrogen; halogen, OH, SH, NH2; an aliphatic radical, which is
linear or branched, saturated or unsaturated, and optionally at least
mono-substituted by F, Cl, Br, I, SH or OH; or O--R with R being an
aliphatic radical, which is linear or branched, saturated or unsaturated,
and optionally at least mono-substituted by F, Cl, Br, I, SH or OH;

[0449]R8 and R8a are independently from each other selected from
hydrogen; or an aliphatic radical, which is linear or branched, saturated
or unsaturated, and optionally at least mono-substituted by F, Cl, Br, I,
SH or OH;

[0450]R9 and R9a are independently from each other selected from
an aliphatic radical, which is linear or branched, saturated or
unsaturated, and optionally at least mono-substituted by F, Cl, Br, I, SH
or OH; or O--R with R being an aliphatic radical, which is linear or
branched, saturated or unsaturated, and optionally at least
mono-substituted by F, Cl, Br, I, SH or OH; or R9 and R9a both
are identical and selected from F, or Cl;

[0451]preferably R9 and R9a are independently from each other
selected from an aliphatic radical, which is linear or branched,
saturated or unsaturated, and optionally at least mono-substituted by F,
Cl, Br, I, SH or OH; or O--R with R being an aliphatic radical, which is
linear or branched, saturated or unsaturated, and optionally at least
mono-substituted by F, Cl, Br, I, SH or OH;

[0452]optionally in form of one of its stereoisomers, preferably
enantiomers or diastereomers, its racemate or in form of a mixture of at
least two of its stereoisomers in any mixing ratio, or in form of a salt,
preferably a physiologically acceptable salt thereof, or a solvate, or
N-oxide, respectively, for the manufacture of a medicament for the
treatment of a 5-HT7 mediated disease or condition.

[0453]In a preferred embodiment the use according to the invention relates
to at least one compound according to formula Ia,

##STR00100##

wherein

[0454]A is a compound selected from the following group

##STR00101##

preferably

##STR00102##

[0455]R1 and R2 each are independently selected from the group
consisting of hydrogen; or a linear or branched, saturated or
unsaturated, optionally at least mono-substituted aliphatic radical; or

[0456]R1 and R2 together with the bridging nitrogen atom form an
saturated or unsaturated, optionally at least mono-substituted 5- or
6-membered-heterocyclic ring, which may be condensed with an optionally
at least mono-substituted mono- or polycyclic ringsystem,

[0457]R3 and R4 are independently from each other selected from
hydrogen; halogen, OH, SH, NH2; a linear or branched, saturated or
unsaturated, optionally at least mono-substituted aliphatic radical; or
O--R with R being a linear or branched, saturated or unsaturated,
optionally at least mono-substituted aliphatic radical;

[0458]R6 and R7 are independently from each other selected from
hydrogen; halogen, OH, SH, NH2; an aliphatic radical, which is
linear or branched, saturated or unsaturated, and optionally at least
mono-substituted by F, Cl, Br, I, SH or OH; or O--R with R being an
aliphatic radical, which is linear or branched, saturated or unsaturated,
and optionally at least mono-substituted by F, Cl, Br, I, SH or OH;

[0459]R8 and R8a are independently from each other selected from
hydrogen; or an aliphatic radical, which is linear or branched, saturated
or unsaturated, and optionally at least mono-substituted by F, Cl, Br, I,
SH or OH;

[0460]R9 and R8a are independently from each other selected from
an aliphatic radical, which is linear or branched, saturated or
unsaturated, and optionally at least mono-substituted by F, Cl, Br, I, SH
or OH; or O--R with R being an aliphatic radical, which is linear or
branched, saturated or unsaturated, and optionally at least
mono-substituted by F, Cl, Br, I, SH or OH; or R9 and R8a both
are identical and selected from F, or Cl;

[0461]preferably R9 and R8a are independently from each other
selected from an aliphatic radical, which is linear or branched,
saturated or unsaturated, and optionally at least mono-substituted by F,
Cl, Br, I, SH or OH; or O--R with R being an aliphatic radical, which is
linear or branched, saturated or unsaturated, and optionally at least
mono-substituted by F, Cl, Br, I, SH or OH;

[0462]optionally in form of one of its stereoisomers, preferably
enantiomers or diastereomers, its racemate or in form of a mixture of at
least two of its stereoisomers in any mixing ratio; or in form of a salt,
preferably a physiologically acceptable salt thereof, or a solvate, or
N-oxide, respectively, for the manufacture of a medicament for the
treatment of a 5-HT7 mediated disease or condition.

[0463]In a preferred embodiment the use according to the invention relates
to at least one compound according to formula Ia,

##STR00103##

wherein

[0464]A is a compound selected from the following group

##STR00104##

preferably

##STR00105##

[0465]R1 and R2 each are independently selected from the group
consisting of hydrogen; or a linear or branched, saturated or
unsaturated, optionally at least mono-substituted aliphatic radical; or

[0466]R1 and R2 together with the bridging nitrogen atom form an
saturated or unsaturated, optionally at least mono-substituted 5- or
6-membered-heterocyclic ring, which may be condensed with an optionally
at least mono-substituted mono- or polycyclic ringsystem,

[0467]R3 and R4 are independently from each other selected from
hydrogen; halogen, OH, SH, NH2; a linear or branched, saturated or
unsaturated, optionally at least mono-substituted aliphatic radical; or
O--R with R being a linear or branched, saturated or unsaturated,
optionally at least mono-substituted aliphatic radical;

[0468]R6 is selected from hydrogen; halogen, OH, SH, NH2; an
aliphatic radical, which is linear or branched, saturated or unsaturated,
and optionally at least mono-substituted by F, Cl, Br, I, SH or OH; or
O--R with R being an aliphatic radical, which is linear or branched,
saturated or unsaturated, and optionally at least mono-substituted by F,
Cl, Br, I, SH or OH;

[0469]R9 and R9a are independently from each other selected from
an aliphatic radical, which is linear or branched, saturated or
unsaturated, and optionally at least mono-substituted by F, Cl, Br, I, SH
or OH; or O--R with R being an aliphatic radical, which is linear or
branched, saturated or unsaturated, and optionally at least
mono-substituted by F, Cl, Br, I, SH or OH; or R9 and R9a both
are identical and selected from F, or Cl;

[0470]preferably R9 and R9a are independently from each other
selected from an aliphatic radical, which is linear or branched,
saturated or unsaturated, and optionally at least mono-substituted by F,
Cl, Br, I, SH or OH; or O--R with R being an aliphatic radical, which is
linear or branched, saturated or unsaturated, and optionally at least
mono-substituted by F, Cl, Br, I, SH or OH;

[0471]optionally in form of one of its stereoisomers, preferably
enantiomers or diastereomers, its racemate or in form of a mixture of at
least two of its stereoisomers in any mixing ratio; or in form of a salt,
preferably a physiologically acceptable salt thereof, or a solvate, or
N-oxide, respectively, for the manufacture of a medicament for the
treatment of a 5-HT7 mediated disease or condition.

[0472]The present invention also provides for the use of at least one
compound according to the invention according to formula (I) or (Ia),
optionally in form of one of its stereoisomers, preferably enantiomers or
diastereomers, its racemate or in form of a mixture of at least two of
its stereoisomers in any mixing ratio; or in form of salt, preferably a
physiologically acceptable salt thereof, or a solvate, or N-oxide,
respectively, for the manufacture of a medicament for the treatment of a
5-HT7 mediated disease or condition.

[0473]In a preferred embodiment the use according to the invention relates
to a use, wherein the disease is pain, preferably visceral pain, chronic
pain, cancer pain, migraine, acute pain or neuropathic pain, more
prefearably neuropathic pain, allodynia or hyperalgesia.

[0475]The medicament/pharmaceutical composition may be in any form
suitable for the application to humans and/or animals, preferably
mammals, and can be produced by standard procedures known to those
skilled in the art. The composition of the medicament may vary depending
on the route of administration.

[0476]The medicament of the present invention may e.g. be administered
parentally in combination with conventional injectable liquid carriers,
such as water or suitable alcohols. Conventional pharmaceutical adjuvants
for injection, such as stabilizing agents, solubilizing agents, and
buffers, may be included in such injectable compositions. These
medicaments may preferably be injected intramuscularly,
intraperitoneally, or intravenously.

[0477]Medicaments according to the present invention may also be
formulated into orally administrable compositions containing one or more
physiologically compatible carriers or excipients, in solid or liquid
form. These compositions may contain conventional ingredients such as
binding agents, fillers, lubricants, and acceptable wetting agents. The
compositions may take any convenient form, such as tablets, pellets,
capsules, lozenges, aqueous or oily solutions, suspensions, emulsions, or
dry powdered form suitable for reconstitution with water or other
suitable liquid medium before use, for immediate or controlled release.

[0478]The liquid oral forms for administration may also contain certain
additives such as sweeteners, flavoring, preservatives, and emulsifying
agents. Non-aqueous liquid compositions for oral administration may also
be formulated, containing e.g. edible oils. Such liquid compositions may
be conveniently encapsulated in e.g., gelatin capsules in a unit dosage
amount.

[0479]The compositions of the present invention may also be administered
topically or via a suppository.

[0480]The above mentioned compositions include preferably 1 to 60% by
weight of one or more of the compound of general formula (I), optionally
in form of one of its stereoisomers, preferably enantiomers or
diastereomers, its racemate or in form of a mixture of at least two of
its stereoisomers in any mixing ratio, or a physiologically acceptable
salt thereof, or a solvate, respectively, and 40 to 99% by weight of the
appropriate pharmaceutical vehicle(s).

[0481]The daily dosage for humans and animals may vary depending on
factors that have their basis in the respective species or other factors,
such as age, weight or degree of illness and so forth. The daily dosage
for mammals including humans usally ranges from 1 milligram to 2000
milligram, preferably 1 to 1500 mg, more preferably 1 to 1000 mg of
substance to be administered during one or several intakes.

[0482]Thus, the invention also provides a method of treatment using the
medicament/pharmaceutical compositions described above.

[0483]Pharmacological Methods:

[0484]Radioligand Binding

[0485]Radioligand binding assays were performed using the Cloned Human
Serotonin Receptor, Subtype 7 (h5HT7), expressed in CHO cells,
coated on Flashplate (Basic FlashPlate Cat.: SMP200) from PerkinElmer
(Cat.: 6120512). The protocol assay was essentially the recommended
protocol in the Technical Data Sheet by PerkinEmer Life and Analytical
Sciences. The Mass membrane protein/well was typically 12 pg and the
Receptor/well was about 9-10 fmoles. The Flashplate were let equilibrate
at room temperature for one hour before the addition of the components of
the assay mixture. The binding buffer was: 50 mM Tris-HCl, pH 7.4,
containing 10 mM MgCl2, 0.5 mM EDTA and 0.5% BSA. The radioligand
was [125I]LSD at a final concentration of 0.82 nM. Nonspecific
binding was determined with 50 μM of Clozapine. The assay volume was
25 μl. TopSeal-A were applied onto Flashplate microplates and they
were incubated at room temperature for 240 minutes in darkness. The
radioactivity were quantified by liquid scintillation spectrophotometry
(Wallac 1450 Microbeta Trilux) with a count delay of 4 minutes prior to
counting and a counting time of 30 seconds per well. Competition binding
data were analyzed by using the LIGAND program (Munson and Rodbard,
LIGAND: A versatile, computerized approach for characterization of
ligand-binding systems. Anal. Biochem. 107: 220-239, 1980) and assays
were performed in triplicate determinations for each point.

[0486]Functionality assay on the 5HT7 receptor were done according to
those known in the state of the art.

[0487]The following examples are given to illustrate the present
invention, but they do not limit the scope of the present invention.

EXAMPLES

[0488]A general scheme which was followed in general terms allowing for
variants in preparing the examples is shown below:

##STR00106##

[0489]Base, Catalyst/Ligand, solvent as well as temperature and reaction
time could vary.

[0492]In a more general form Example 1 was prepared according to the
following Scheme

##STR00108##

[0493]Base, Catalyst, Solvent, Temperature and reaction time in the last
step, a so-called "Suzuki Reaction" were varied and in part orientated on
literature such as JACS, 2002, 1162 and Angew. Chem. Int. Ed. 2006, 1282.

[0495]The Temperature was usually 10° C. and the Reaction Time
varied between a few minutes and 20 hours and even microwave irridation
was used.

[0496]Yields varied between 8% and 78%.

[0497]After its precursors (A and B) were prepared Example 1 was
synthesized following different methods explained more in detail below:

Example A

[2-(3-Bromo-phenyl)-ethyl]-methyl-amine

##STR00109##

[0499]2-(3-Bromo-phenyl)-ethylamine (0.5 mmol) and formaldehyde (0.42
mmol) were mixed in 3 ml of 1,2-dichloroethane in a process vial, which
was sealed with a septum. Sodium triacetoxyborohydride (0.84 mmol) was
added under argon atmosphere. The suspension was subjected to microwave
irradiating conditions (CEM Discover® equipped with a CEM
Explorer® automated reaction handling module). The reaction mixture
was heated for 5 min at 90° C. and then cooled. The crude was
evaporated to dryness and then suspended in aqueous NaHCO3. The
product was extracted with CH2Cl2 and washed with aqueous
NaHCO3. The CH2Cl2 extract was dried with anhydrous
Na2SO4, filtered and evaporated to dryness to give the crude
product [2-(3-bromo-phenyl)-ethyl]-methyl-amine. The crude was purified
by flash column chromatography (CH2Cl2-MeOH as eluents) by
using a CombiFlash Companion® system to yield the title compound (75%)
as colourless oil.

Example B

[2-(3-Bromo-phenyl)-ethyl]-dimethyl-amine

##STR00110##

[0501](Method 1) 2-(3-Bromo-phenyl)-ethylamine (0.5 mmol) and formaldehyde
(2.5 mmol) were mixed in 5 ml of 1,2-dichloroethane in a process vial,
which was sealed with a septum. Sodium triacetoxyborohydride (1 mmol) was
added under argon atmosphere. The suspension was subjected to microwave
irradiating conditions (CEM Discover® equipped with a CEM
Explorer® automated reaction handling module). The reaction mixture
was heated for 5 min at 120° C. and then cooled. The crude was
evaporated to dryness and then suspended in aqueous NaHCO3. The
product was extracted with CH2Cl2 and washed with aqueous
NaHCO3. The CH2Cl2 extract was dried with anhydrous
Na2SO4, filtered and evaporated to dryness to give the crude
product [2-(3-bromo-phenyl)-ethyl]-dimethyl-amine. The crude was purified
by flash column chromatography (CH2Cl2-MeOH as eluents) by
using a CombiFlash Companion® system to yield the title compound (86%)
as colourless oil.

[0502](Method 2): 2-(3-Bromo-phenyl)-ethylamine (50 mmol) and formaldehyde
(250 mmol) were mixed in 170 ml of 1,2-dichloroethane. Sodium
triacetoxyborohydride (100 mmol) was added under argon atmosphere. The
suspension was stirred at 120° C. for 1 h and then cooled. Aqueous
NaHCO3 was added to the reaction mixture and the organic layer was
separated and washed with aqueous NaHCO3. The organic extract was
dried with anhydrous Na2SO4, filtered and evaporated to dryness
to give the crude product [2-(3-bromo-phenyl)-ethyl]-dimethyl-amine. The
crude was purified by flash column chromatography (CH2Cl2-MeOH
as eluents) by using a CombiFlash Companion® system to yield the title
compound (90%) as colourless oil.

Example 1

Dimethyl-{2-[3-(1,3,5-trimethyl-1H-pyrazol-4-yl)-phenyl]-ethyl}-amine

##STR00111##

[0504](Method 1): [2-(3-Bromo-phenyl)-ethyl]-dimethyl-amine (0.44 mmol)
was dissolved in DME/H2O 1/1 (8 mL) under argon atmosphere.
1,3,5-Trimethyl-1H-pyrazole-4-boronic acid pinacol ester (0.66 mmol),
K2CO3 (2.19 mmol), and tetrakis-(triphenylphosphine)palladium
(10 mol %, 0.044 mmol) were added and the reaction mixture was stirred at
100° C. for 20 h. The reaction mixture was evaporated to dryness,
then dissolved in CHCl3 and filtered through Celite® to give the
crude product
dimethyl-{2-[3-(1,3,5-trimethyl-1H-pyrazol-4-yl)-phenyl]ethyl}-amine. The
crude was purified by flash column chromatography (CH2Cl2-MeOH
as eluents) by using a CombiFlash Companion® system to yield the title
compound (60%) as colourless oil.

[0505](Method 2): [2-(3-Bromo-phenyl)-ethyl]-dimethyl-amine (0.22 mmol)
was dissolved in DME/H2O 1/1 (4 mL) under argon atmosphere in a
process vial. 1,3,5-Trimethyl-1H-pyrazole-4-boronic acid pinacol ester
(0.33 mmol), K2CO3 (1.1 mmol), and
tetrakis-(triphenylphosphine)palladium (10 mol %, 0.022 mmol) were added
and the vial was sealed with a septum. The reaction mixture was subjected
to microwave irradiating conditions, heated for 5 min at 100° C.
and then cooled. The reaction mixture was evaporated to dryness, then
dissolved in CHCl3 and filtered through Celite® to give the
crude product
dimethyl-{2-[3-(1,3,5-trimethyl-1H-pyrazol-4-yl)-phenyl]-ethyl}-amine.
The crude was purified by flash column chromatography
(CH2Cl2-MeOH as eluents) by using a CombiFlash Companion®
system to yield the title compound (78%) as colourless oil.

[0506](Method 3): [2-(3-Bromo-phenyl)-ethyl]-dimethyl-amine (0.44 mmol),
1,3,5-trimethyl-1H-pyrazole-4-boronic acid pinacol ester (0.876 mmol),
tris(dibenzylideneacetone)dipalladium (5 mol %, 0.022 mmol) and DPEPhos
(6 mol %, 0.026 mmol) were dissolved in dioxane. K3PO4 (1.32
mmol) dissolved in 4 mL of water was added to the mixture and the
reaction was stirred at 100° C. for 20 h. The reaction mixture was
evaporated to dryness, then dissolved in CHCl3 and filtered through
Celite® to give the crude product
dimethyl-{2-[3-(1,3,5-trimethyl-1H-pyrazol-4-yl)-phenyl]-ethyl}-amine.
The crude was purified by flash column chromatography
(CH2Cl2-MeOH as eluents) by using a CombiFlash Companion®
system to yield the title compound (24%) as colourless oil.

[0507](Method 4): [2-(3-Bromo-phenyl)-ethyl]-dimethyl-amine (0.44 mmol),
1,3,5-trimethyl-1H-pyrazole-4-boronic acid pinacol ester (0526 mmol),
tris(dibenzylideneacetone)dipalladium (2 mol %, 0.009 mmol) and
tricyclohexylphosphine (4.8 mol %, 0.021 mmol) were dissolved in 4 mL of
dioxane. K3PO4 (0.745 mmol) dissolved in 4 mL of water was
added to the mixture and the reaction was stirred at 100° C. for
20 h. The reaction mixture was evaporated to dryness, then dissolved in
CHCl3 and filtered through Celite® to give the crude product
dimethyl-{2-[3-(1,3,5-trimethyl-1H-pyrazol-4-yl)-phenyl]-ethyl}-amine.
The crude was purified by flash column chromatography
(CH2Cl2-MeOH as eluents) by using a CombiFlash Companion®
system to yield the title compound (8%) as colourless oil.

[0508](Method 5): [2-(3-Bromo-phenyl)-ethyl]-dimethyl-amine (0.44 mmol),
1,3,5-trimethyl-1H-pyrazole-4-boronic acid pinacol ester (0526 mmol),
tris(dibenzylideneacetone)dipalladium (4.3 mol %, 0.019 mmol) and DPEPhos
(10 mol %, 0.044 mmol) were dissolved in 4 mL of dioxane. K3PO4
(2.19 mmol) dissolved in 4 mL of water was added to the mixture and the
reaction was stirred at 100° C. for 20 h. The reaction mixture was
evaporated to dryness, then dissolved in CHCl3 and filtered through
Celite® to give the crude product
dimethyl-{2-[3-(1,3,5-trimethyl-1H-pyrazol-4-yl)-phenyl]-ethyl}-amine.
The crude was purified by flash column chromatography
(CH2Cl2-MeOH as eluents) by using a CombiFlash Companion®
system to yield the title compound (34%) as colourless oil.

[0509](Method 6): [2-(3-Bromo-phenyl)-ethyl]-dimethyl-amine (17.5 mmol)
was dissolved in DME/H2O 1/1 under argon atmosphere.
1,3,5-Trimethyl-1H-pyrazole-4-boronic acid pinacol ester (17.5 mmol),
K2CO3 (52.6 mmol), and tetrakis-(triphenylphosphine)palladium
(2 mol %, 0.35 mmol) were added and the reaction mixture was stirred at
100° C. for 3.5 h. Then, a second fraction of
1,3,5-trimethyl-1H-pyrazole-4-boronic acid pinacol ester (5.2 mmol) was
added and the reaction mixture was stirred at 100° C. for 2 h
more. The reaction mixture was evaporated to dryness, then dissolved in
CH2Cl2 and filtered through Celite®. The filtrate was
acidified with HCl aqueous solution (6 N). The organic layer was
discarded, and the aqueous layer was taken to pH >13 with NaOH aqueous
solution (6 N). It was extracted with CH2Cl2 (3×300 mL),
and the organic layer was dried over anhydrous Na2SO4, filtered
and concentrated, to give the crude product
dimethyl-{2-[3-(1,3,5-trimethyl-1H-pyrazol-4-yl)-phenyl]ethyl}-amine. The
crude was purified by flash column chromatography (CH2Cl2-MeOH
as eluents) by using a CombiFlash Companion® system to yield the title
compound (60%) as colourless oil.

[0510](Method 7): [2-(3-Bromo-phenyl)-ethyl]-dimethyl-amine (1.25 mmol)
and magnesium (1.3 mmol) were placed in a microwave vial under nitrogen
in dry tetrahydrofuran. The suspension was irradiated for 20 min at
120° C. Separately, 4-bromo-1,3,5-trimethyl-1H-pyrazole (1 mmol),
PEPPSI-SIPr (2 mol %, 0.021 mmol) and lithium chloride (3.20 mmol) were
dissolved in anhydrous THF and purged with nitrogen. While stirring this
suspension, the Grignard reagent solution was added via a syringe. The
reaction was stirred at 50° C. for 4 h and then it was quenched in
0.1 M HCl. Then MTBE was added and the suspension was basified to pH 11
with 1N NaOH and filtered through Celite®. The filtrate was extracted
with CH2Cl2, and the organic layer was dried over anhydrous
Na2SO4, filtered and concentrated, to give the crude product.
The crude was purified by flash column chromatography
(CH2Cl2-MeOH as eluents) to yield the title compound
dimethyl-{2-[3-(1,3,5-trimethyl-1H-pyrazol-4-yl)-phenyl]-ethyl}-amine
(74%) as colourless oil.

[0512]Dimethyl-{2-[3-(1,3,5-trimethyl-1H-pyrazol-4-yl)-phenyl]-ethyl}-amin-
e was diluted in ethyl acetate and a solution of hydrogen chloride 2.0 M
in diethylether was added. The resulting precipitate was filtered and
dried under vacuum to yield the title compound
dimethyl-{2-[3-(1,3,5-trimethyl-1H-pyrazol-4-yl)-phenyl]-ethyl}amine
dihydrochloride (98%).

Example 2

Methyl-{2-[3-(1,3,5-trimethyl-1H-pyrazol-4-yl)-phenyl]-ethyl}-amine

##STR00113##

[0514]To a solution of tert-butyl
3-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenethylcarbamate (0.7 mmol) was
added a solution of LiAlH4 1M in THF (3.5 mmol) and the mixture was
heated to reflux for 1 h. Then, the reaction mixture was cooled to room
temperature and treated with a saturated solution of Rochelle's salt.
After stirring 1 h at room temperature, the mixture was filtered and
concentrated to give the crude product. The crude was purified by flash
chromatography (neutral Al2O3, CH2Cl2-MeOH as
eluents) by using a CombiFlash Companion® system to yield the title
compound methyl-{2-[3-(1,3,5-trimethyl-1H-pyrazol-4-yl)-phenyl]-ethyl}-am-
ine (85%).

Example D 2-[3-(1,3,5-Trimethyl-1H-pyrazol-4-yl -phenyl]-ethylamine

##STR00114##

[0516]2-(3-Bromo-phenyl)-ethylamine (15 mmol) was dissolved in
DME/H2O 1/1 under argon atmosphere.
1,3,5-Trimethyl-1H-pyrazole-4-boronic acid pinacol ester (15 mmol),
K2CO3 (45 mmol), and tetrakis-(triphenylphosphine)palladium (1
mol %, 0.15 mmol) were added and the reaction mixture was stirred at
100° C. for 1.5 h. Then, a second fraction of
1,3,5-trimethyl-1H-pyrazole-4-boronic acid pinacol ester (4.5 mmol) was
added and the reaction mixture was stirred at 100° C. for 2 h
more. The reaction mixture was evaporated to dryness, then dissolved in
CH2Cl2 and filtered through Celite® to give the crude
product 2-[3-(1,3,5-trimethyl-1H-pyrazol-4-yl)-phenyl]-ethylamine. The
filtrate was acidified with HCl aqueous solution (6 N). The organic layer
was discarded, and the aqueous layer was taken to pH >13 with NaOH
aqueous solution (6 N). It was extracted with CH2Cl2
(3×300 mL), and the organic layer was dried over anhydrous
Na2SO4, filtered and concentrated, to give the crude product
2-[3-(1,3,5-trimethyl-1H-pyrazol-4-yl)-phenyl]-ethylamine. The crude was
purified by flash column chromatography (CH2Cl2-MeOH as
eluents) by using a CombiFlash Companion® system to yield the title
compound (80%).

[0518]2-[3-(1,3,5-Trimethyl-1H-pyrazol-4-yl)-phenyl]-ethylamine was
diluted in ethyl acetate and a solution of hydrogen chloride 2,0 M in
diethylether was added. The resulting precipitate was filtered and dried
under vacuum to yield the title compound
2-[3-(1,3,5-trimethyl-1H-pyrazol-4-yl)-phenyl]-ethylamine dihydrochloride
(98%).

Example 6

{2-[3-(3,5-Dimethyl-1H-pyrazol-4-yl)-phenyl]-ethyl}-methyl-amine

##STR00116##

[0520]A solution of
{2-[3-(3,5-dimethyl-1H-pyrazol-4-yl)-phenyl]-ethyl}-dimethyl-amine (1.16
mmol) in methylene chloride and diisopropylethylamine (2.03 mmol) was
treated with 1-chloroethyl chloroformate (2.03 mmol). The reaction
mixture was stirred at room temperature for 2.5 h and then the solvent
was evaporated at reduced pressure and the resulting residue was
dissolved in methanol (3 mL) and heated at reflux for 3 h. The methanol
was then evaporated at reduced pressure and the crude product was
purified by flash chromatography (neutral Al2O3,
CH2Cl2-MeOH as eluents) by using a CombiFlash Companion®
system to yield the title compound
{2-[3-(3,5-dimethyl-1H-pyrazol-4-yl)-phenyl]-ethyl}-methyl-amine (83%).

[0521]The other examples were or are prepared according to or analogous to
the reaction schemes and descriptions given above and are listed (where
applicable) together with their binding data, their Mass and their 1H-NMR
data in the following table: